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G Model

NBR-1575; No. of Pages 41 ARTICLE IN PRESS


Neuroscience and Biobehavioral Reviews xxx (2012) xxxxxx

Contents lists available at SciVerse ScienceDirect

Neuroscience and Biobehavioral Reviews


journal homepage: www.elsevier.com/locate/neubiorev

Review

The role of metaplasticity mechanisms in regulating memory destabilization and


reconsolidation
Peter S.B. Finnie, Karim Nader
Department of Psychology, McGill University, 1205 Avenue du Docteur Peneld, Montreal, Quebec, Canada H3A 1B1

a r t i c l e i n f o a b s t r a c t

Article history: Memory allows organisms to predict future events based on prior experiences. This requires encoded
Received 11 October 2011 information to persist once important predictors are extracted, while also being modiable in response
Received in revised form 9 March 2012 to changes within the environment. Memory reconsolidation may allow stored information to be mod-
Accepted 21 March 2012
ied in response to related experience. However, there are many boundary conditions beyond which
reconsolidation may not occur. One interpretation of these ndings is that the event triggering memory
Keywords:
retrieval must contain new information about a familiar stimulus in order to induce reconsolidation.
Learning and memory
Presently, the mechanisms that affect the likelihood of reconsolidation occurring under these conditions
Memory reconsolidation
Extinction
are not well understood. Here we speculate on a number of systems that may play a role in protecting
Synaptic plasticity memory from being destabilized during retrieval. We conclude that few memories may enter a state in
Metaplasticity which they cannot be modied. Rather, metaplasticity mechanisms may serve to alter the specic reac-
Rats tivation cues necessary to destabilize a memory. This might imply that destabilization mechanisms can
Mice differ depending on learning conditions.
Humans 2012 Elsevier Ltd. All rights reserved.

Contents

1. Introduction to memory consolidation and reconsolidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00


1.1. Reconsolidation in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Mechanisms of memory destabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. When does reconsolidation occur and what is it doing? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.1. Boundary conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2. Functions of reconsolidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2.1. Reconsolidation reects lingering consolidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2.2. Reconsolidation as a mechanism for memory updating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2.3. Partial or complete destabilization of a memory following reactivation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.2.4. Reconsolidation and the similarity of experiences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.3. Constraints on the interpretation of boundary conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3.4. A general principle that could mediate boundary conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Metaplastic processes as mechanisms of memory stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Altered calcium transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.1. NMDA-receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.2. L-type voltage-gated calcium channels (L-VGCCs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.3. Calcium-permeable AMPA receptors (CP-AMPARs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1.4. Summary: different calcium sources for different experiences? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Intrinsic neuronal excitability, and the role of the cholinergic and adrenergic systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2.1. Neuronal excitability controls plasticity and is modulated by experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2.2. Regulation of reconsolidation via neuronal excitability? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2.3. A model for learning-dependent regulation of neuronal excitability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Corresponding author. Tel.: +1 514 398 3511; fax: +1 514 398 4896.
E-mail address: karim.nader@mcgill.ca (K. Nader).

0149-7634/$ see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.neubiorev.2012.03.008

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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NBR-1575; No. of Pages 41 ARTICLE IN PRESS
2 P.S.B. Finnie, K. Nader / Neuroscience and Biobehavioral Reviews xxx (2012) xxxxxx

4.2.4. Adrenergic and cholinergic mechanisms of plasticity and reconsolidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00


4.2.5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3. Mechanisms of synaptic maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3.1. PKM and the regulation of GluR2-containing AMPAR endocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3.2. NR2BCaMKII protein complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4. Population-level mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4.1. Network expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4.2. Hippocampus-mediated novelty-detection and dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.5. Other stability mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.5.1. Group I metabotropic glutamate receptors (mGluRs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.5.2. Epigenetic regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.5.3. Neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.5.4. Extracellular matrix (ECM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.5.5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.6. Converging plasticity pathways? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Clinical relevance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.1. Suppression of maladaptive memories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5.2. Aging and memory loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Conict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction to memory consolidation and 2010 for review). For instance, some older and stronger memo-
reconsolidation ries have been observed not to undergo reconsolidation (Suzuki
et al., 2004), leading several researchers to conclude that it reects
Just over a decade ago a majority of the behavioral neuroscience a lingering consolidation process which may eventually termi-
eld appeared to have concluded that memory, after having been nate (see Alberini, 2011). However, others have noted that the
gradually stored by the brain, was static (see Dudai, 2004). Treat- parameter-space for reactivation may simply be changed under
ment of memories as discrete, stable records of the past engaged these reconsolidation-resistant conditions, as longer (Suzuki et al.,
many researchers in a quest to pinpoint the neuronal mechanisms 2004) or delayed (Wang et al., 2009) reactivation may still engage
responsible for preserving permanent traces, and to identify the cir- reconsolidation. Together this work indicates that there may not
cuits mediating specic engrams (see Kandel, 2001; Squire, 2004). be a fully stable state of memory encoding, and given appropri-
This was based largely on ndings indicating that after a period ate reactivation cues a memory might always be able to re-enter
of memory consolidation, during which a newly acquired memory a modiable state which can resemble the process induced during
was sensitive to disruption, a memory entered a stabilized state its initial consolidation (see Nader and Hardt, 2009). It also sug-
in which it was no longer susceptible to disruption by the same gests that certain training procedures must evoke a shift in the
amnesic agents (McGaugh, 1966). Although cognitive traditions mechanisms that initiate plasticity which prevents reconsolida-
had long argued for the malleability of memory after storage (at tion from being induced by some reactivation protocols by which
least in humans; Bartlett, 1932; Loftus et al., 1978), the prevailing it is normally engaged, while still permitting reactivation by other
opinion in neuroscience seemed to suggest that this was mediated methods.
by a set of static encoding mechanisms (McGaugh, 1966). Indeed, we have observed that two days after training, the reac-
However, following a long, sparse history of research into a tivation of a very strong auditory fear memory does not induce its
phenomenon now known as reconsolidation (i.e. Misanin et al., reconsolidation (Wang et al., 2009). This reconsolidation-resistant
1968; Lewis, 1979; see Sara, 2000), a surge of papers at the turn state was characterized by the down-regulation of a mechanism
of the millennium brought about a rapid and dramatic shift in our (NR2B-containing NMDARs in basolateral amygdala) known to be
appreciation of memory not necessarily as a permanent storage required to induce reconsolidation of this type of memory (Ben
medium, but as a dynamic encoding process (Nader et al., 2000; Mamou et al., 2006). However, if the animal had its hippocampus
Przybyslawski and Sara, 1997). Considerable neurobiological evi- lesioned prior to training or if the memory was reactivated 60 days
dence now indicates that memory is quite malleable not just at the after training, baseline NR2B expression was observed and recon-
level of behavioral expression (Hupbach et al., 2007) but also at cel- solidation of this strong memory could be induced as normal. Thus,
lular and synaptic levels (e.g. Doyre et al., 2007; Lee et al., 2011). it appears that changes to the molecular mechanisms mediating
The occurrence of reconsolidation has largely been supported by memory destabilization might control the reactivation conditions
observations that following the retrieval of a previously consoli- necessary to induce reconsolidation. This may be a behavioral man-
dated memory, the delivery of amnestic drugs (Debiec et al., 2002), ifestation of a phenomenon known as metaplasticity: the plasticity
electroconvulsive shock (Lewis, 1979; Lewis and Bregman, 1973; of synaptic plasticity (Abraham and Bear, 1996). Specically, learn-
Misanin et al., 1968), interfering information (Hupbach et al., 2009), ing may induce metaplastic changes at synaptic connections that
or other types of manipulations (Mactutus et al., 1979; Rose and encode a given memory, which could change the types of behav-
Rankin, 2006) can impair its subsequent retention. Moreover, it has ioral experience necessary to reactivate this trace and induce its
been demonstrated that memory can also be enhanced during its reconsolidation.

retrieval (Debiec et al., 2011; DeVietti et al., 1977; J.L.C. Lee et al., The primary purpose of this review is to speculate on how
2006; Tian et al., 2011) or perhaps even modied to incorporate several different metaplasticity mechanisms (including NR2B
new information (Choi et al., 2010; Lee, 2010). down-regulation) might allow the brain to accomplish this
However, it is also clear that not every memory will undergo selective memory stability. We rst review evidence that recon-
reconsolidation each time it is retrieved (see Nader and Einarsson, solidation occurs in humans, and address recent criticisms of this

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
G Model
NBR-1575; No. of Pages 41 ARTICLE IN PRESS
P.S.B. Finnie, K. Nader / Neuroscience and Biobehavioral Reviews xxx (2012) xxxxxx 3

work (Section 1.1). In Section 2 we comprehensively summarize the have used pharmacological interventions have administered the
mechanisms that have been reported to be necessary for memory non-toxic -adrenergic antagonist propranolol (Brunet et al., 2008;
reconsolidation to be induced (such as amygdala NR2B activity). Kindt et al., 2009; Soeter and Kindt, 2010, 2011b). Consistently,
We then review the conditions under which memories have been these studies have found evidence for a pharmacological blockade
observed to not undergo reconsolidation (Section 3.1) and present of emotional aspects of a memory during reconsolidation. Thus,
evidence indicating that the function of reconsolidation might be there is overwhelming, almost exponentially growing evidence for
to update memory with related information (Section 3.2). In Sec- reconsolidation: Between 2000 and 2005, there was only one paper
tion 3.3 we discuss why purported reconsolidation boundaries published using humans to categorically demonstrate reconsoli-
suffer from an interpretive limitation (as it is always possible that dation (Walker et al., 2003). Between the years 2005 and 2010,
an untested reactivation parameter could induce reconsolidation), sixteen more were published reporting evidence consistent with
and reintroduce a general molecular approach, based on the afore- reconsolidation.
mentioned ndings by Wang and colleagues, to identify when a Opposing these conclusions, a critical and rigorous review
memory is in a reconsolidation-resistant state. In brief, we propose was recently published by Schiller and Phelps (2011), which re-
that NR2B down-regulation in BLA might serve to prevent induc- examined the evidence supporting the existence of reconsolidation
tion of memory lability, and thus could act as a marker for when a in humans. The authors state in their paper while research with
memory will not undergo reconsolidation. non-human animals has produced over 300 papers just in the last
Section 4 serves less as a review, and more as a theoretical pro- 10 years, human research provided about 13 [p. 2] (at the date of
posal to speculate on brain mechanisms that could mediate the submission of their review we counted closer to eighteen). While
hypothesized memory stability system presented in the prior sec- we agree that more studies examining human reconsolidation
tions. Little translational research exists on this topic, thus we draw would be a great asset to the eld, its recent rate of growth provides
mechanisms primarily from physiological studies that might per- reason for optimism. For example, one could compare the number
mit or prevent the destabilization of memories during reactivation. of papers on human reconsolidation that were published between
Where possible we have attempted to connect this work to related 1968 and 1978 (the decade following the initial study on recon-
behavioral experiments, but in several instances relevant work has solidation, Misanin et al., 1968) to the papers that were published
not yet been reported. Thus we advise readers to interpret these between 2000 and 2010 (the decade following the revival of recon-
mechanisms with caution they are presented merely to inspire solidation by Nader et al., 2000; Sara, 2000, and others). Between
others to consider the infrequently discussed links between mech- 1968 and 1978, three papers were published, while eighteen were
anisms of memory reconsolidation and metaplasticity. Finally, in published between 2000 and 2010. From this historical perspective
Section 5 we hypothesize how these mechanisms might be rele- the number of publications alone allows us to be very optimistic,
vant to the study of clinical topics. Identifying the conditions and and we expect many new approaches will help unveil this phe-
mechanisms regulating memory stability is of critical importance nomenon. For instance, a recent study by Schwabe et al. (2011)
to our understanding of how our experiences are integrated into a found that administration of a -adrenergic receptor antagonist
general knowledge about the world. before reactivation selectively impairs the subsequent memory for
emotional events. Using functional magnetic resonance imaging
1.1. Reconsolidation in humans (fMRI), these authors showed that this emotional memory impair-
ment was accompanied by systematic changes in the amygdala
The collection of reconsolidation research that has been con- and the hippocampus- structures that were also recruited during
ducted in humans has become quite impressive. Although it was reactivation.
originally debated whether reconsolidation could even occur in One conceptual issue raised by Schiller and Phelps against the
humans (Dawson and McGaugh, 1969; Squire et al., 1976), this phe- human reconsolidation literature could stem from their interpreta-
nomenon has now been robustly demonstrated for many tasks. For tions of work by Lewis (1979). His conceptualization incorporates
example, it has been shown to occur for motor skill tasks (Walker consolidation and reconsolidation into a single memory process
et al., 2003), episodic/declarative memory (Forcato et al., 2007; that stabilizes with time. He postulated that memories in an
Hupbach et al., 2009), and fear conditioning (Kindt et al., 2009). active (unstable) state could include both new and reactivated
Typically in these studies, post-reactivation amnesia is induced traces. Both new and reactivated memories were proposed to stabi-
via interference by competing new learning or by stress. Com- lize over time into inactive memory states. Because this denition
pared to reconsolidation studies in animals, only a small number of active states does not differentiate new and reactivated memo-
of groups have used pharmacological approaches. At submission of ries, alternative interpretations of reconsolidation studies should
this review there were more than 20 papers on reconsolidation in also apply to consolidation studies, and vice versa. We also infer
humans that were published since the revival of reconsolidation at that his basic theory should apply to all tasks, species, and amnesic
the turn of the millenium (Brunet et al., 2008; Censor et al., 2010; agents.
Chan et al., 2009; Coccoz et al., 2011; Forcato et al., 2007, 2009, Referring to Lewis seminal work on memory, Schiller and Phelps
2010, 2011; Hupbach et al., 2007, 2008, 2009; Kindt et al., 2009; state that these studies established the criteria to which an exper-
Schiller et al., 2010; Schwabe and Wolf, 2009, 2010; Schwabe et al., imental protocol of reconsolidation should obey: (1) Reactivate a
2011; Soeter and Kindt, 2010, 2011a,b; Strange et al., 2010; Walker consolidated memory by means of a reminder cue; (2) Administer
et al., 2003; Zhao et al., 2009). Most of these papers are essentially the treatment aimed at altering reconsolidation post reactivation
consistent with the general hypothesis of reconsolidation, with and not prior to it; (3) Test for retention after the effects of the
many clear demonstrations of post-reactivation effects on memory treatment have dissipated and the window of reconsolidation has
retention. These demonstrations include memory enhancements closed. Stemming from these interpretations, the authors suggest
by naturalistic stressors (Coccoz et al., 2011), memory impairments that studies with pre-reactivation infusions, therefore, do not meet
by stress (Schwabe and Wolf, 2010; Strange et al., 2010), or interfer- the rigorous standards proposed by Lewis. For the logical reasons
ence protocols that induce amnesia (Hupbach et al., 2007; Walker described above, however, this stipulation should then apply to all
et al., 2003). One study tested the hypothesis that reconsolidation memories in an active state (hence not just to reconsolidation but
can facilitate the formation of false memories (see Hardt et al., also to consolidation). Thus, if we accept the proposition of these
2010 for a relevant discussion), and found evidence consistent with authors then we must discount what can be inferred from all stud-
that suggestion (Chan et al., 2009). The majority of studies that ies using pre-learning or pre-reactivation amnesic agents. These

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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agents include pharmacological interventions, but also inducible clinical trials are extremely expensive and time consuming; there-
knockouts animals, virus infusions, antisense oligonucleotides, and fore, it seems reasonable to apply pharmacological treatments at
mutant mice (in which the protein of interest is not present either times that could maximize amnesic effects. Again, we encour-
prior to learning/reactivation or a subsequent retention test). age others to accept pre-learning/reactivation approaches (as did
However, having re-read Lewis we are hard pressed to nd Lewis), so long as the manipulations being used do not affect
evidence which asserts the second and third criteria as a requi- retrieval of the memory trace.
site either for consolidation or reconsolidation experiments. We Schiller and Phelps are also correct in pointing out that the eld
feel that with careful controls, it is unnecessary to draw such of reconsolidation is inconsistent based on ndings using propra-
apparently articial lines between pre- and post-reactivation infu- nolol. However, we anticipate that as more data is procured, the
sions. Pre-learning or pre-reactivation amnesic agents have been sources of these inconsistencies will be revealed. Later in this paper
administered hundreds of times since the inception of the eld of (Sections 3 and 4) we will theorize on how some mechanisms,
experimental amnesia. For example, in McGaughs (1966) paper including propranolol, could be sufcient to impair reconsolidation
on consolidation perhaps one third of the pharmacological studies or to block the induction of reconsolidation depending on training
cited were given prior to learning. This procedure did not invalidate and reactivation procedures.
the ndings for consolidation. McGaugh states, either pre-or post- These authors also make important arguments that remind us
training injections, the degree of impairment of retention increases of the interpretive limits of the fear conditioning results in humans.
directly with increases in the dose of puromycin injected. This nd- They cite the ndings that fear potentiated startle but not declar-
ing is interesting in view of evidence that the duration of protein ative knowledge of a toneshock contingency could be impaired
synthesis inhibition varies directly with the dose of puromycin by pre-reactivation propranolol (Kindt et al., 2009). However, this
[p. 1353]. Here, he refers to the classic paper by Agranoff et al. again raises the point that reconsolidation impairments need not
(1965), which was among the rst demonstrating the role of pro- be expected across all conditioned responses or all memory types.
tein synthesis in memory consolidation. Pre-training procedures For instance, conditioning parameters that are required to induce
have been successfully used more recently as well, for example, by freezing and fear potentiated startle are rather different in ani-
Cahill and McGaugh (Cahill et al., 1994), who infused propranolol mals. Freezing can be acquired with a single stimulusfootshock
prior to learning in order to study its inuence on consolidation. pairing (e.g. Nader et al., 2000), while fear potentiated startle
Lewis had a similar openness to consideration of ndings from often takes two days with 15 trials per day to elicit a reliable
experiments using pre-learning/pre-reactivation administration of baseline response (Falls and Davis, 1995; Nader et al., 2000). The
amnesic agents. For example, he states [. . .] injections of the pro- differences in conditioning parameters could predict different sen-
tein synthesis inhibitor cycloheximide (cyclo) before learning did sitivities to specic consolidation or reconsolidation challenges, as
not prevent normal initial acquisition nor did it interfere with the pharmacological studies reviewed by Schiller and Phelps clearly
memory until several hours (36) had passed (Barondes and Cohen, highlight. These authors suggest that differential effects on sev-
1968a,b), by which time severe memory decrements had been eral fear responses indicate that pre-reactivation treatments have
observed. Thus cyclo seemed to be acting specically on LTM while in some way impaired response expression rather than disrupting
leaving STM intact (Lewis, 1979, p. 1061). From this it appears that fear memory itself. However, the different strengths of train-
he accepted pre-reactivation manipulation as a valid approach to ing required to support fear potentiated startle versus other fear
the study of memory (re)consolidation. responses could alter the sensitivity of these memories to specic
Studies in the reconsolidation eld have often required the drugs, like propranolol. In this way, one training procedure may
use of pre-reactivation manipulations. For example, some amnesic produce a memory sensitive to adrenergic blockade, while another
agents such as inhibitory antisense oligonucleotides take some may not. In fact, the remainder of this review will be dedicated to
time in order to lower protein levels. Several papers by Lee (J.L.C. Lee discussing how reconsolidation mechanisms might be expected to
et al., 2004; Lee, 2008) used pre-reactivation antisense treatments vary dramatically under different training and reactivation condi-
in order to allow enough time for the levels of protein to decrease. tions.
In genetically modied mice the protein of interest is missing from
birth and thus prior to reactivation. However, even in this system
clever approaches have been devised to control for this potential 2. Mechanisms of memory destabilization
confound (Bozon et al., 2003). Phelps and Schiller are correct in
warning that care must be taken when viewing the results of pre- Between instances of consolidation and reactivation, memories
reactivation amnesic treatments. The appropriate control for this is may be at least somewhat stable, in that they are not sensitive to
to ensure that the acquired response assessed during reactivation the same amnesic manipulations as observed during these labile
is not affected. The animal studies mentioned above (Bozon et al., phases (see Alberini, 2005). One important question that stems
2003; J.L.C. Lee et al., 2004; Lee, 2008), and the human study by from this work is how some types of memories are able to transition
Kindt et al. (2009) incorporate this important control. We can have from this stable storage state back to a labile (destabilized) state
faith that these controls are sufciently rigorous, as the same effect following retrieval. Using a procedure developed by Ben Mamou
has also been observed when propranolol was administered after et al. (2006), which allows for the dissociation of memory destabi-
reactivation (Soeter and Kindt, 2011b). lization (or the induction of lability) from the restabilization of this
Reconsolidation induced by re-exposure to a conditioned cue trace during reconsolidation, several mechanisms have been iden-
may take less time than consolidation following learning (Nader, tied. In the traditional reconsolidation procedure, it is assumed
2003). These retrograde gradients observed after reconsolidation that induction of memory reconsolidation has occurred if post-
challenge can range from 2 s to hours after reactivation, depend- reactivation amnesic agents impair its retention. Therefore, we
ing on the parameters of the experiment, including amnesic agents have reasoned that if the inhibition of a mechanism prior to reac-
(Mah and Albert, 1973). Therefore, if one were to give a drug sys- tivation prevented the effects of amnesic treatments administered
temically following reactivation, one might miss the brief window after memory reactivation, then this would indicate that induction
of instability. As long as a drug does not impact responding during of lability had been blocked. Applying this logic, we have found
the retrieval of the memory, then we feel that pre-reactivation drug the mechanisms mediating memory destabilization could be dou-
administration is a reasonable approach to maximize the chances bly dissociated from the mechanisms that mediate the behavioral
of the drug being present during reconsolidation. Human and expression of the memory.

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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Specically, it was demonstrated that if memory destabilization destabilization mechanisms within the amygdala and hippocam-
was prevented by infusing a selective antagonist of the N-methyl-d- pus. For example, Suzuki, Kida and colleagues have found
aspartate receptor (NMDAR) subunit NR2B (now known as GluN2B) that L-type voltage-gated calcium channels (L-VGCCs) and
prior to reactivation, then an amnesic agent (the protein synthe- endocannabinoid type-1 (CB1) receptors are required in the hip-
sis inhibitor anisomycin) infused into the basolateral amygdala pocampus to destabilize contextual fear conditioning (Suzuki
(BLA) immediately after reactivation failed to impair the reten- et al., 2008) and spatial watermaze (Kim et al., 2011) memories.
tion of this memory. This suggested that NR2B-containing NMDARs Specically, animals infused with the selective L-VGCC antagonist,
are necessary to initiate a plasticity process which destabilizes nimodipine, or the CB1 antagonist, SR141716A, into the dorsal hip-
auditory fear memories and returns them to a labile, anisomycin- pocampus prior to an unreinforced reactivation session retained
sensitive state. This is consistent with in vitro work demonstrating that memory even when anisomycin was infused immediately after
the involvement of NMDARs in the induction of many forms of plas- retrieval. Interestingly, for these hippocampus-dependent tasks it
ticity (Malenka and Nicoll, 1993). NR2B-subunits in particular may seems that NMDARs are not required for destabilization, but only
be important because they enable greater calcium transmission for restabilization or reconsolidation of the trace. Both NMDARs and
(Sheng et al., 1994; Sobczyk et al., 2005), which is one reason that L-VGCCs may permit the entry of calcium, which can act as a second
they may be required for conditioned fear acquisition (Rodrigues messenger to activate many plasticity processes. For example, cal-
and Schafe, 2001) and extinction (Sotres-Bayon et al., 2007). It is cium can activate calmodulin and calcium/calmodulin-dependent
also interesting to note that application of the NMDAR-agonist, protein kinase II (CaMKII), which may induce the activation and
d-cycloserine (DCS), has been observed to potentiate the recon- translocation of the proteasome to the post-synaptic density for
solidation of aversive and appetitive memories (J.L.C. Lee et al., degradation of membrane proteins (Bingol et al., 2010; Djakovic
2006, 2009). These ndings could indicate that promoting NMDAR et al., 2009), which might be necessary for memory destabilization
activity could facilitate the destabilization process. (Kaang and Choi, 2011).
However, the dependence of destabilization on NMDAR activ- In agreement with this position, protein degradation via the
ity does not seem to be consistent across memory types and ubiquitinproteasome system has been shown to be necessary for
brain regions. Although there is little debate about the require- the induction of reconsolidation in the hippocampus (Choi et al.,
ment of NMDARs for reconsolidation (Przybyslawski and Sara, 2010; Kaang and Choi, 2011; Lee, 2008; Lee et al., 2008) and amyg-
1997; Torras-Garcia et al., 2005), several studies have reported dala (Jarome et al., 2011). When Lee and colleagues infused the
that NMDAR antagonists infused into the BLA impair retention proteasome inhibitor, -lactacystin (Lac), into the hippocampus
of appetitive (Lee and Everitt, 2008) and drug (Milton et al., prior to re-exposure to the training context, it prevented the post-
2008a) memories, though perhaps only when infused prior to reac- reactivation impairments otherwise induced by post-reactivation
tivation. One possible explanation for the differential effects of anisomycin infusions into the BLA. In a related manner, it has been
NMDAR-antagonists on reconsolidation is that these appetitive and reported that blocking the proteasome in the hippocampus pre-
drug-related memories were acquired via much longer (and pos- vents the strengthening of already consolidated contextual fear
sibly stronger) training procedures. In these studies, rats received memories during an additional conditioning session in the same
as many as 300 pairings of conditioned and unconditioned stimuli, context, as well as impairments induced by anisomycin infusions
while rats in the Ben Mamou study received just one toneshock during this training (Lee, 2008). More recently it was also observed
pairing. As will be discussed in detail in Section 3, this could induce that the proteasome can prevent the updating of a mnemonic
a switch in plasticity induction mechanisms, resulting in a reduced representation of a recently experienced context during exposure
reliance on NR2Bs for destabilization. In partial support of this to footshock in the same context (Lee, 2010). Similarly, updating
position, a study by Brown et al. (2008a) demonstrated that an the memory of four familiar objects when the location of two was
NMDAR-antagonist can impair reconsolidation of a conditioned swapped was found to be impaired by dorsal hippocampal pro-
place preference memory (acquired via 4 pairings of cocaine and teasome inhibition, although in this case it appeared that the new
context), but not cocaine self-administration (acquired over many locations were encoded but not properly integrated with the exist-
tens or hundreds of pairings of lever-press and cocaine). However, ing location memory (Choi et al., 2010). Together these ndings
this explanation based on training-strength is entirely speculative. provide convincing evidence that destabilization of a memory can
Another potential explanation for the differential effects could be require degradation of the proteins mediating its encoding (Kaang
general differences in mechanism required for these very different and Choi, 2011). In fact, an explanation for the nding that induc-
types of emotional memory. For example, in the crab Chasmag- tion of reconsolidation can initially induce a transient reduction
nathus it has been observed that the endogenous biogenic amine in training-induced eld potentials (Clarke et al., 2010; Rao-Ruiz
octopamine, which is related to norepinephrine and can affect et al., 2011) could be that removal and degradation of synap-
dopaminergic and adrenergic systems in vertebrates, has differ- tic receptors may be required for memory to be altered, though
ent roles in the consolidation and reconsolidation of appetitive this link is not yet conclusively established. Interestingly, Jarome
versus aversive memories (Kaczer et al., 2011). Even more relevant et al. (2011) recently found that expression of a marker of protein
is the very recent report that within the rat nucleus accumbens, degradation (polyubiquitination) mirrored upregulation of protein
pre-reactivation infusion of NMDAR antagonist blocks reconsolida- synthesis during memory consolidation, and that polyubiquitina-
tion of morphine conditioned place preference, but not conditioned tion of specic proteins involved in translational regulation and
place aversion (Wu et al., 2012). Thus, in at least two brain regions synaptic structure occurred during reconsolidation a process that
there may be differential involvement of NMDARs in reconsol- was dependent on NR2B activity. This suggests that protein degra-
idation of aversive and appetitive memories. It is not yet clear dation is likely a downstream mechanism of NR2B activation. They
what could drive NMDAR-independent destabilization of some observed that post-training infusion of Lac into BLA impaired con-
types of memories, though several possibilities are discussed next textual and auditory fear memory consolidation, and post-retrieval
with respect to hippocampus. In the hippocampus it has also been it prevented the destabilization of both types of consolidated mem-
observed that NMDARs are critical for memory restabilization, but ory.
application of an NMDAR-antagonist does not prevent the induc- Finally, preliminary evidence indicates that the protein phos-
tion of reconsolidation (Suzuki et al., 2008). phatase 2B (also known as PP2B, PPP3CA, and calcineurin) may
The procedure introduced by Ben Mamou has since been also be necessary to return memory to a labile state (Kim
elegantly modied to identify a number of other important et al., unpublished results). When infused into the amygdala or

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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hippocampus immediately following brief re-exposure to a previ- 2011), when it is indirectly related to the memory being assessed
ously fear conditioned context, a selective inhibitor of calcineurin
(Debiec et al., 2006) or, as stated above, when it is presented at
has been observed to prevent the amnesia induced by anisomycin long intervals after training. It has also recently been reported in
infusion. This preliminary work paints a complex picture of the one elegant study that reactivation during sleep is an additional
process, as calcineurin activation is also thought to play a role in condition under which sensitivity to interference is not observed
the switch from reconsolidation to extinction mechanisms during (Diekelmann et al., 2011).
long unreinforced reactivation (de la Fuente et al., 2011). How- For most of these boundary conditions, however, there have
ever, de la Fuente and colleagues observed no effect of hippocampal been inconsistent ndings. These include evidence for reconsolida-
infusion of the selective calcineurin inhibitor, FK-506, on memory
tion of old (Debiec et al., 2002; Diergaarde and Schoffelmeer, 2006;
retention when this occurred following a short reactivation pro- J. Lee et al., 2006; Robinson and Franklin, 2010; Romero-Granados
cedure, which is what would be expected if calcineurin is in fact et al., 2010; Wang et al., 2009) and strongly trained memories
necessary for destabilization. It has also recently been reported that (Suzuki et al., 2004; Wang et al., 2009). Specically, remote or
calcineurin inhibition facilitates new spatial watermaze learning, strongly trained memories may be rendered labile by longer reac-
but also slows reversal learning (Shaw et al., 2012), a procedure pre- tivation sessions (Suzuki et al., 2004; Frankland et al., 2006) or by
viously observed to induce reconsolidation (Rossato et al., 2006). exposure to novel stimuli at reactivation (Lee, 2010; Winters et al.,
Although Shaw and colleagues argued that this impairment could 2009). Furthermore, it has been observed that strong memories
be due to impaired extinction of the original platform location, we can undergo reconsolidation if they are reactivated at remote time-
feel that it is just as likely to be due to impaired modication of points (Robinson and Franklin, 2010; Wang et al., 2009). Finally, it
the existing memory to include the new information present at has been shown that even extinction may not prevent the induc-
reactivation. tion of reconsolidation (Duvarci et al., 2006; Prez-Cuesta and
The ndings reported in this section reveal that several distinct Maldonado, 2009; Stollhoff et al., 2005). This nal point is worth
mechanisms may each be necessary to initiate memory recon- elaborating on, as extinction per se may not be a boundary.
solidation. It is not yet clear in what way these systems may Extinction has long been interpreted not as the weakening or
interact, though calcium inux via NR2Bs or L-VGCCs may trig- erasure of a previously acquired memory, but rather as the for-
ger calcineurin and proteasome activity, after which destabilization mation of a new, inhibitory trace that in some manner competes
may be induced. Assessing other downstream and upstream pro- with or suppresses the original memory (see Bouton, 2004). Indeed,
cesses will be important to fully understand how destabilization is it appears that as unreinforced exposure to a previously condi-
mediated, and which proteins need to be targeted for this process tioned stimulus gradually begins to reduce responding, infusions of
to occur. However, it has been observed that under certain condi- amnestic drugs cease to disrupt memory retention/reconsolidation
tions types of memories that normally undergo reconsolidation no and begin to disrupt the newly forming inhibitory trace (Eisenberg
longer do so, suggesting that the destabilization mechanisms dis- et al., 2003; Suzuki et al., 2004). This phenomenon has been referred
cussed above may somehow be disabled in some situations. These to as trace dominance and proposes that the memory driving
conditions are discussed next. behavior may be primarily susceptible to disruption at retrieval
(Eisenberg et al., 2003). Thus, extinction may preclude reconsolida-
tion because it encodes a new, independent memory trace. A recent
3. When does reconsolidation occur and what is it doing? modeling study has concluded that the transition which can occur
during re-exposure to a conditioned stimulus (CS) may work along
3.1. Boundary conditions a novelty continuum (Osan et al., 2011). As an animal progresses
through a long unreinforced CS exposure, it may transition from
Many so-called boundary conditions have been observed, mere memory retrieval, to reconsolidation, to extinction, which
beyond which reconsolidation appears not to occur (Dudai may simply be related to the degree of similarity or novelty that
and Eisenberg, 2004). These have been comprehensively sum- exists between the re-exposure session and the initial training.
marized elsewhere (see Nader and Hardt, 2009; Tronson and It is not surprising then that extinction memories themselves
Taylor, 2007), but include characteristics of the learning ses- have been observed to undergo reconsolidation following reacti-
sion, the reactivation session, and interactions between the two. vation (Rossato et al., 2010), which suggests that these inhibitory
Characteristics of a consolidated memory that seem to impede traces may be just like other memories. In this sense, extinction
reconsolidation include its age (Baratti et al., 2008; Eisenberg itself may not be a boundary per-se, but rather, the boundary
and Dudai, 2004; Frankland et al., 2006; Milekic and Alberini, is the formation of a new memory. Supporting this position,
2002; Suzuki et al., 2004), training strength (Eisenberg et al., exposure to a familiar context containing only new or only previ-
2003; Suzuki et al., 2004; Taylor et al., 2009; Wang et al., 2009; ously experienced objects does not induce lability of this memory,
Winters et al., 2009), when learning has reached an asymptote while a familiar context containing one new and one old object
(Garcia-DeLaTorre et al., 2009; Lee, 2010; Morris et al., 2006; does (Rossato et al., 2007). Also Rodrguez-Ortiz et al. (2005)
Rodrguez-Ortiz et al., 2005, 2008), and others (Biedenkapp and have reported that once learning that a specic avored liquid
Rudy, 2004). (saccharin solution) is safe to drink reaches an asymptote, it is
Characteristics of the reactivation session may also exist as resistant to disruption during additional exposures to saccharin.
boundaries to the induction of reconsolidation. Reconsolidation At near asymptotic responding, pairing malaise-inducing lithium-
may not occur when a reactivation stimulus consists of a very chloride with consumption of this liquid reduced its subsequent
short (Bustos et al., 2009; Lagasse et al., 2009) or long (Eisenberg consumption, but additional reduction of consumption due to
et al., 2003; J.L.C. Lee et al., 2006; Mamiya et al., 2009; Pedreira a second lithium-chloride pairing was impaired by the infusion
and Maldonado, 2003; Prez-Cuesta and Maldonado, 2009; Suzuki of anisomycin. In fact, the consumption of liquid increased in
et al., 2004) duration of exposure to a reminder, as when extinction this group, indicating that trace dominance caused anisomycin
is induced (Inda et al., 2005; Power et al., 2006; Rossato et al., 2006; to impair only the active aversive memory trace. This supports
Tronson et al., 2006). It also may not be induced when reactivation the position that with sufcient novelty, a familiar experience
occurs in a new environment (DeVietti and Holiday, 1972; Hupbach can be encoded as a new, dissociable trace. It should be noted
et al., 2008), when it is predictable (Forcato et al., 2009; Morris that these authors interpret their ndings as evidence for a phe-
et al., 2006; Osan et al., 2011; Pedreira et al., 2004; Robinson et al., nomenon they refer to as consolidation-update, which differs

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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from reconsolidation in that it does not imply a complete reca- synaptic reentry reinforcement (Wittenberg et al., 2002), wherein
pitulation of the consolidation process, but rather the encoding reactivation during awake experience or during rest may induce
and integration of new information with existing knowledge via processes that facilitate the establishment and modication of Heb-
destabilization of only relevant parts of the neural ensemble that bian associations between previously experienced stimuli, in order
encodes a memory (see Rodriguez-Ortiz and Bermudez-Rattoni, to extract biologically signicant predictors (Rasch and Born, 2007;
2007; Rodrguez-Ortiz et al., 2008). This implies a gradient of desta- Sara, 2010). Lingering consolidation is also partially supported by
bilization during memory reactivation rather than an all-or-none the occurrence of retrograde amnesia, wherein recent memory is
phenomenon. generally more susceptible to loss than remote memory that has
Regardless of the process engaged, it appears that encoding of had more time to fully stabilize (Squire and Bayley, 2007).
a new trace has the ability to prevent destabilization of the ini- Under this rationale it has also been suggested that cases
tially retrieved trace in a manner that is not at all understood. of memory updating should often be mediated via the forma-
In the case of extinction, mechanisms of reconsolidation could be tion and consolidation of a new trace (Alberini, 2011). Citing
engaged early in a reactivation session, and after a certain length dissociable mechanisms of consolidation and reconsolidation
of time extinction mechanisms may be engaged, inhibiting recon- (inhibitory avoidance consolidation requires transcription factor
solidation from proceeding. This might involve suppression of the CCAAT enhancer binding protein [C/EBP] in the hippocampus,
transcription factor nuclear factor-B (NF-B) (de la Fuente et al., but reconsolidation requires C/EBP in the amygdala (Taubenfeld
2011; Merlo et al., 2005; Merlo and Romano, 2008), activation of et al., 2001; Tronel et al., 2005), Tronel and colleagues showed
CB1 receptors (Alvares et al., 2008), or alterations in calcineurin that acquisition of a second-order inhibitory avoidance task is not
activity (de la Fuente et al., 2011). It is also possible that either prevented by blocking amygdalar C/EBP (Tronel et al., 2005).
reconsolidation or extinction is engaged only at the termination of Specically, animals trained to avoid a section of a chamber
a reactivation session (i.e. offset of a CS), which would each induce containing a salient visual cue (light), a process which required hip-
plasticity mechanisms in functionally distinct neural ensembles pocampal C/EBP activity, could transfer this response to another
(see Pedreira et al., 2004 for related ndings). chamber when the light was presented during the rats exposure to
Complicating this boundary further, if reconsolidation of a trace this environment (known as second-order conditioning). Blocking
has already progressed beyond a certain point (perhaps the removal C/EBP in amygdala had no effect on acquisition of this second-
or degradation of synaptic proteins), it might not be possible to order response. However, it impaired retention of the previously
prevent this destabilization, and thus the new learning (extinc- acquired rst-order memory. The interpretation presented by these
tion or otherwise) may be mediated by an alteration of the original authors was that linking new information to a fear memory could
memory trace. Specically, when extinction follows shortly after a induce its reconsolidation, but the second-order trace was encoded
reactivation session, some researchers have found that this mem- independently as a new memory trace. This was taken as evidence
ory does not exhibit evidence for the return of a conditioned that updating a memory relies on consolidation. However, whether
response (Clem and Huganir, 2010; Flavell et al., 2011; Monls second-order conditioning would even be expected to induce
et al., 2009; Rao-Ruiz et al., 2011; Schiller et al., 2010), such as memory updating is debatable, as it is conceptualized to involve
spontaneous recovery, reinstatement, or renewal, which are nor- the formation of a direct association between the second-order CS
mally observed for extinguished memories (Bouton, 2004). This has and the unconditioned stimulus that is resistant to extinction of
led some to conclude that post-reactivation extinction works via the rst-order CS (Rizley and Rescorla, 1972; Rodrguez-Ortiz et al.,
reconsolidation-update to permanently weaken (Monls et al., 2008; Tronson and Taylor, 2007). Furthermore, as will be discussed
2009; Rao-Ruiz et al., 2011) or even erase (Clem and Huganir, next, other work has recently demonstrated that updating an exist-
2010; Maren, 2011) the memory trace. However, this effect has not ing memory (the representation of a conditioning chamber) during
been consistently observed by all researchers (Chan et al., 2010; immediate shock in this environment engages reconsolidation-
Costanzi et al., 2011; Soeter and Kindt, 2011a). specic mechanisms in the hippocampus (Lee, 2010).

3.2. Functions of reconsolidation 3.2.2. Reconsolidation as a mechanism for memory updating


The second major theory of reconsolidation function stems from
The boundaries discussed above have collectively led to two the aforementioned evidence that old and/or strongly encoded
semi-distinct theories regarding the function of reconsolidation memories at learning asymptote can still be made labile by expo-
(see Alberini, 2011; Davis et al., 2010 for discussion). Both support sure to novel, unexpected, or long reactivation stimuli. It is also
the idea that a malleable phase following retrieval could serve an based on ndings like those of Hupbach and colleagues, which show
important function in maintaining memory relevance in a chang- that newly learned items can intrude into old knowledge if exist-
ing environment: infrequently reactivated memories may decay, ing memories are rst retrieved (Hupbach et al., 2007). Together
while those that continue to be necessary (as evidenced by their this work has led some authors to conclude that memory may be
continued retrieval and usefulness to predict outcomes) will be maintained in a permanently modiable form which permits the
preserved. updating of each trace when relevant new information is encoun-
tered (Abraham and Robins, 2005; Dudai, 2004, 2009; Forcato et al.,
3.2.1. Reconsolidation reects lingering consolidation 2010; Hupbach et al., 2008; Jones et al., 2012; Lee, 2009; Lukowiak
Evidence that older or stronger memories (i.e. those at a puta- et al., 2007; Morris et al., 2006; Sara, 2000; Tronson and Taylor,
tive learning asymptote) are not destabilized by reactivation has 2007).
led some to conclude that reconsolidation may simply be involved We feel that these two theories of reconsolidation function
in an extended, lingering consolidation process (Alberini, 2005, (strengthening of consolidation and memory updating) are not
2011; Dudai and Eisenberg, 2004). This is partially based on obser- entirely incompatible. It is quite clear that the age and strength of
vations that over time, learned responses gradually strengthen, a a memory can indeed make it more resistant to destabilization fol-
phenomenon known as incubation (Eysenck, 1968; Gabriel, 1968; lowing some types of reactivation, but it appears that this resistance
Pickens et al., 2009), and is further bolstered by reports that might not apply to all possible reactivation parameters (Lee, 2010;
repeated reactivations can accelerate incubation (Forcato et al., Suzuki et al., 2004; Winters et al., 2009). To reconcile these posi-
2011) and the progression of a memory toward a reconsolidation- tions, several authors have proposed that reconsolidation should
resistant state (Inda et al., 2011). This could be due to a process like only occur when the actual features or outcomes of an event do

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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not match what was predicted based upon past experience (Lee, memory update but also impaired the previously encoded context
2009; Wang and Morris, 2010). For instance, when a watermaze memory. Those animals infused with zif268 antisense at immedi-
platform is no longer in the previous location, or when a well- ate shock exposure could not be retrained by a later immediate
explored environment contains new features. This is founded on shock session, while animals that had merely undergone block-
the work of Rescorla and Wagner (1972), which suggests that sur- ade of reconsolidation update by proteasome inhibition were later
prise will dictate when learning occurs. If an animal continues to able to acquire a contextual fear response. Finally, animals already
learn incrementally over successive encounters with a task, then strongly fear-conditioned to the training context did not undergo
this should be added to the memory of the previous trial (see Wang reconsolidation when given immediate shock in this environ-
and Morris, 2010). In this way, even repeated trials of the same ment. Together these ndings indicate that learning which has
training procedure could induce reconsolidation as long as there reached asymptotic levels can still be labilized by exposure to an
is still something new to learn (Morris et al., 2006; Rodrguez- unpredicted outcome. Most critically, encoding of the unexpected
Ortiz et al., 2005, 2008). For instance, Lee (2008) demonstrated event in a familiar context relies on purportedly reconsolidation-
that a weakly trained contextual fear memory was strengthened via specic mechanisms. Blocking these mechanisms disrupted both
reconsolidation when another conditioning trial was administered updating and retention of the previously consolidated context
in the same context. However, an efcient biological system would memory.
not be expected to expend energy in re-encoding information that The ndings of Lee clearly differ from those of Tronel and
is already adequately stored. In this way, reconsolidation should colleagues (albeit using a different task). First, Lee found that
cease to occur when additional exposures to a task closely match consolidation and reconsolidation processes require distinct mech-
what is encoded, which may be reected in the tendency of brain anisms within a single brain region (J.L.C. Lee et al., 2004), instead of
activity to be reduced over multiple exposures to the same event the same mechanism in different regions. Second, Lee observed that
(see Grill-Spector et al., 2006). Importantly, additional training may both strengthening a contextual memory trace and the addition
not be necessary to bring a sub-asymptotic learned response to of a new conditioned response induced and required reconsolida-
asymptote. As discussed above, time may be sufcient to allow suf- tion. Tronel and colleagues might have predicted that this process
cient ofine reactivation for the brain to identify and strengthen should be mediated by consolidation of a distinct memory, and
task-relevant information to an asymptote (see Inda et al., 2011). that blocking reconsolidation would have disrupted retention of
Several studies support these predictions. Morris et al. (2006) the context memory representation. It is not simple to reconcile
and Rodrguez-Ortiz et al. (2008) each demonstrated that when these inconsistent ndings, though we expect that the Tronel study
animals were given more training trials in a watermaze task, their may have utilized a procedure that causes a direct association
memories were not rendered labile by the same reactivations that between a second-order stimulus and a fear response that does
destabilized more weakly trained memories. In a similar manner, not directly rely on the updating of the existing associative mem-
Winters et al. (2009) reported that changing the texture of oor- ory.
ing during a reactivation trial was sufcient to induce lability of a Evidence that old memories may be labilized and updated by
well-trained object recognition memory that would not undergo new information presented during reactivation is not as direct
reconsolidation during additional exposure to the objects in the
(Wichert et al., 2011). Debiec et al. (2002) showed that even
unaltered context (Winters et al., 2009). Furthermore, although 45-day-old contextual fear memories could be impaired by ani-
it might be expected that over time a weak recognition memory somycin infusion after unreinforced context exposure, but the role
should fade, Winters reported that when reactivation was deliv- for memory updating in this task is not conclusive. Some stud-
ered two days after training, instead of one, inclusion of the novel ies using an apparatus called the event arena provide evidence for
ooring was necessary to induce lability. Although other valid the rapid incorporation of new information into gradually acquired
interpretations of these result have been presented (see Alberini, schemas via a process that is reminiscent of reconsolidation (Tse
2011), we feel that the simplest explanation is that the new et al., 2007, 2011). In this task it was found that training rats to
ooring requires remodeling of the well-encoded Y-maze context nd specic foods at specic spatial locations for each of several
representation via reconsolidation-mediated memory update, the different avor cues resulted in gradually improved performance
disruption of which also impairs retrieval of the object memories. in a manner that required a functional hippocampus through-
Perhaps the most convincing evidence that reconsolidation out the weeks of training. Once the task was well acquired, new
serves to update memory with new information comes from Lees odorlocation pairs could be rapidly encoded in a manner that was
(2010) recent study, mentioned previously. Here he demonstrated only briey hippocampus-dependent. Importantly, it was observed
that short exposure to a conditioning chamber allowed additional that this rapid incorporation only occurred when new paired-
re-exposure to induce reconsolidation. This was indicated by a associates were presented in the same environment, which might
reduced capacity for this context representation to subsequently serve to reactivate the proper memory trace (Tse et al., 2007). Fur-
facilitate fear conditioning during an immediate footshock proce- thermore, exposure to only new or only old pairs did not induce the
dure (Fanselow, 1986) if this re-exposure was preceded by infusion same increase of IEG expression in various cortical regions (prelim-
of a drug known to selectively disrupt reconsolidation in hippocam- bic and retrosplenial cortices) that was observed when two new
pus (zif268 antisense; see J.L.C. Lee et al., 2004). If animals had pairs were presented after several old pairs (Tse et al., 2011). This
already been given a long exploration session, presumably suf- suggests that retrieval of the old pairs prior to new encoding might
cient to encode this environment, additional exposure did not have facilitated incorporation of new information into schemas
induce reconsolidation, as evidenced by insensitivity to zif268 via plasticity of an existing cortical memory network. Critically,
antisense infusion. However, the well-encoded context memory it could also indicate that the gradual transition of memory into
could be labilized when animals were given immediate shock in cortical regions over weeks or months of training might not pre-
this environment, indicating that task-relevant novelty at the time vent its updating when relevant new information is encountered
of reactivation could cause reconsolidation. This update of the (as will be discussed in Section 4.4.1). Indeed, retrieval of these
context memory to include the footshock relied on hippocampal rapidly encoded pairs 24 h after training was impaired by infusion
immediate early gene (IEG) zif268 but not BDNF activity, which of an AMPAR antagonist into the prelimbic cortex, which might not
have been shown to be necessary for reconsolidation and consol- be predicted for newly acquired hippocampus-dependent memo-
idation, respectively (J.L.C. Lee et al., 2004). When zif268 activity ries if updating is mediated by consolidation. Moreover, lesioning
was inhibited during immediate shock, it not only prevented the the hippocampus 48 h after rapid encoding of new pairs had no

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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effect on retention, which suggests that these memories had rapidly an experience that are not already well encoded (or that are
transitioned to a cortically mediated state. new). This position would also predict that the more dissimi-
This work does not directly implicate reconsolidation, but if lar a reactivation cue is to a memory, the smaller portion of
future studies were to demonstrate that exposure to new paired that memory will be destabilized to encode the new information,
associates induced lability of the well-trained old pairs in cortical although this position is not yet strongly supported empiri-
regions, then it would provide convincing evidence. To further dis- cally.
sociate whether updating of the schema relied on reconsolidation,
it could be assessed whether blocking the proteasome pathway in 3.2.4. Reconsolidation and the similarity of experiences
cortical regions or hippocampus during the training of new pairs One parsimonious way of conceptualizing the results dis-
would impair their acquisition. If so, would inhibiting zif268 in hip- cussed in Section 3.2 is that mis-match between the memory
pocampus during the presentation of new pairs block this form of a previously experienced event and a current episode might
of memory updating? Related work in our lab indicates that hip- determine whether or not reconsolidation will be observed
pocampus and cortical regions (anterior cingulate) work together (Pedreira et al., 2004), as elegantly modeled by Osan et al.
to process the storage and reconsolidation of remote contextual (2011). A large degree of similarity (i.e. when additional train-
fear memories (Einarsson, Pors, and Nader, unpublished observa- ing is presented to an animal at behavioral asymptote for
tions). that task) may fail to induce consolidation and reconsolida-
tion entirely, as no new information need be encoded. A small
3.2.3. Partial or complete destabilization of a memory following degree of similarity between a memory and reactivation (i.e.
reactivation? when extinction is induced) may engage memory encoding,
This discussion also highlights our considerable uncertainty but may not cause the destabilization of an existing memory,
about how independently encoded memories about similar stim- and will instead establish a new memory trace. This position
uli or events can be integrated and retrieved (see the discussion of would predict that only moderate task-related novelty will engage
updating-consolidation by Rodriguez-Ortiz and Bermudez-Rattoni, reconsolidation (or will destabilize enough of the trace that its dis-
2007). One possibility is that reactivation of a memory may ruption causes a behavioral impairment, as reviewed in Section
only destabilize part of the trace. Although an amnesic treat- 3.2.3).
ment may block this labile portion, the other parts could remain However, at a behavioral level this hypothesis presents a prob-
intact. Under some conditions (for instance, when anisomycin is lem for empirical falsiability. For instance, when a weakly fear
applied after extinction) it might be expected that this remain- conditioned animal is given unreinforced re-exposure to the CS,
ing unlabilized portion of the memory could mediate expression a short presentation may only engage retrieval (the CS presen-
of the behavior being measured, and thus it might be inter- tation is; Biedenkapp and Rudy, 2004), but a long re-exposure
preted that reconsolidation has not been induced when it actually may induce extinction (Eisenberg et al., 2003). When a moder-
has. ate duration is used, perhaps unencoded information about the
As one example, Debiec and colleagues demonstrated that in CS is stored or the feared CS acts as its own secondary reinforcer
a second-order auditory fear conditioning task (in which an audi- to strengthen the memory, engaging reconsolidation. But what is
tory tone [CS1] was associated with shock, then this CS was paired a moderate CS duration? Providing an independent measure for
with another distinct tone [CS2]), fear responding to CS1 was mis-match, other than the occurrence of reconsolidation itself, is
not impaired when reconsolidation was disrupted by BLA appli- a necessary requirement. Without one, whether or not a reactiva-
cation of anisomycin after CS2 re-exposure. However, responding tion cue matches a given memory is dependent on the observation
to both CS1 and CS2 was impaired when anisomycin was infused of reconsolidation. This might be complicated more so following
after CS1 reactivation. This suggests that these memory traces strong training, when the re-exposure duration capable of evok-
might exist within a network that can be either partially or ing reconsolidation may shrink or close altogether (Suzuki et al.,
entirely labilized depending on the reactivation cue used. Simi- 2004), potentially because the animal can acquire no new infor-
larly, Winters et al. (2011) recently demonstrated that anisomycin mation about the predictive relationship. In this instance, no CS
infused into perirhinal cortex can impair an object recognition re-exposure duration should be sufcient to initiate reconsolida-
memory following reactivation that included one novel object, a tion. Rather, other types of mis-match might be necessary during
novel contextual feature, or re-exposure to the original objects in reactivation; perhaps revaluation of the US (Wang et al., 2005) or
context. However, only reactivation that included a new contex- inclusion of new physical features during the task (i.e. Rossato et al.,
tual feature (a textured oor insert) was impaired by anisomycin 2007). Thus, dening what constitutes similarity or dissimilarity
infused into hippocampus. Although the authors hypothesized could be immensely complicated, so we present this interpreta-
that the altered context apparently causes a reorganization of tion only as a simple explanation of conditions that may induce
the memory into a hippocampus-dependent state, another inter- reconsolidation.
pretation is that not all of the memory is destabilized when In summary, we feel that the weight of the evidence falls
aspects of it are modied. Instead, the hippocampal-mediated in support of the position that reconsolidation mediates mem-
portion of the trace is only destabilized by context-related nov- ory updating when task-related novelty is experienced. Although
elty. If only hippocampal infusions had been used, it would factors like strength or age can apparently decrease the suscepti-
have appeared that only new contextual information engaged bility of a memory to undergo reconsolidation when reactivation
reconsolidation of this type of memory. Critically this result also is similar to training, one possibility is that novel information
demonstrates that blocking the labilized hippocampus-mediated might always be able to destabilize at least part of a related
portion still impairs the putatively perirhinal-mediated memory trace.
for the objects. Relatedly, Rodriguez-Ortiz and Bermudez-Rattoni
(2007) have proposed that as a learning asymptote is approached, 3.3. Constraints on the interpretation of boundary conditions
progressively less of a trace may return to a vulnerable state
during re-exposure to the task, as evidenced by a decreasing From the aforementioned behavioral studies there is a clear
impairment induced by post-reactivation application of amnesic interpretive limitation when attempting to identify true recon-
treatments. Thus, the neuronal ensemble mediating the mem- solidation boundary conditions. Typically boundary conditions
ory may only be partially destabilized to update aspects of are concluded to exist if application of post-reactivation amnesic

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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agents does not lead to an impairment (Dudai and Eisenberg, 2004; destabilize, thereby keeping them in a stable state in which they are
Milekic and Alberini, 2002). But in most studies only a single insensitive to amnesic agents after reactivation, while still allowing
reactivation procedure has been used. Thus, the evidence for the them to be expressed behaviorally.
transformation of a trace from a normal labile state to a static form As discussed previously, we have shown that the mechanisms
is based on negative ndings with a single reactivation procedure. mediating destabilization within the BLA can be dissociated from
The problem is confounded by the fact that there is no single uni- those mediating expression of the learned behavior (Ben Mamou
versally effective reactivation procedure that is always observed to et al., 2006). Infusing the NR2B antagonist ifenprodil into the
induce reconsolidation. We know that different reactivation pro- BLA prior to memory reactivation prevented fear memory from
cedures can have different efcacies at inducing reconsolidation destabilizing, making it insensitive to post-reactivation amnesic
(DeVietti and Holiday, 1972; Lee, 2010; Suzuki et al., 2004). Tak- treatment, although the conditioned response was still expressed
ing the elegant study by Kidas group (Suzuki et al., 2004), which during reactivation (a phenotype similar to memories at puta-
examined the effects of training strength on the ability of a mem- tive boundary conditions). Thus we reasoned that the presence or
ory to undergo reconsolidation, it was reported that contextual absence of the NR2B subunit could act as a molecular indicator for
fear memories acquired with one pairing of context and shock whether or not a memory would undergo reconsolidation.
were sensitive to post-reactivation infusions of anisomycin into In order to test the application of this approach to nd
dorsal hippocampus. Memories acquired with three shocks, how- convergence between behavioral and molecular markers of recon-
ever, were insensitive to the identical amnesic treatment. If these solidation, Wang et al. (2009) performed a number of parametric
authors had stopped there and interpreted the data they may have behavioral experiments to identify how strength of training can
suggested that memory strength is an important regulator of recon- affect the ability of an auditory fear memory to undergo recon-
solidation. The subsequent experiment performed by these authors solidation within the BLA. They found that memories trained with
shows the difculty in interpreting the negative results in the man- 10 toneshock pairings were resistant to post-reactivation amnesic
ner above. The authors tested whether a longer reactivation trial treatments. Three different reactivation procedures each led to neg-
would be able to induce reconsolidation in the memories acquired ative ndings when the memory was reactivated two days after
with three shocks. When the reactivation session was extended, learning. Wang went on to report that the memory returned to a
the stronger memory was observed to undergo reconsolidation. state that was sensitive to post-reactivation amnesic treatments
This is a clear demonstration that a negative nding on some if a 30-day interval was inserted between learning and reactiva-
experimental parameter does not mean the memory cannot tion. Typically when boundary conditions are discussed they are
undergo reconsolidation. This is why as a eld we need a more implicitly discussed as permanent inhibition on reconsolidation.
rigorous approach to this issue. Currently, in some studies, if a neg- Her nding, however, indicates for the rst time that boundary con-
ative nding is obtained using one reactivation procedure, then a ditions may be transient in nature, which has obvious clinical and
boundary conditioning is stated to exist (e.g. Milekic and Alberini, theoretical implications.
2002). However, it will always be possible that another reactiva- We found the time-course of the 30-day transition of mem-
tion procedure could destabilize the memory (for instance, one ory back to a reconsolidation-sensitive state intriguing. When it
that is more or less similar to the original event). Given that the is observed, systems consolidation (the transition of contextual
parameter space for potential reactivation procedures is innite, fear memory from dependent on, to independent of the dorsal hip-
then a purely behavioral approach to describing boundary condi- pocampus) also typically takes approximately 30 days in rodents
tions can only lead to a long list of negative ndings. It does not (Kim and Fanselow, 1992). Given that all conditioning happens
differentiate between a memory that will never undergo reconsol- within a specic environment, contextual conditioning will nat-
idation from one that may simply require a different reactivation urally occur in our auditory fear paradigm. Therefore, we reasoned
protocol. Therefore it remains very difcult to prove using a purely that it was possible that this hippocampus-dependent contex-
behavioral approach that boundary conditions exist. Currently this tual representation could theoretically inhibit reconsolidation of
remains an interpretive limitation for the majority of boundary auditory fear conditioning in the BLA up to approximately 30
conditions identied in the eld. days. To test this hypothesis, Wang gave electrolytic lesions of the
We have recently highlighted a complementary approach to dorsal hippocampus prior to strong training, with the intent of
help resolve this situation. Specically, we aimed to identify impairing the hippocampal representation. The prediction was that
some of the molecular mechanisms that are induced by bound- strong memories should then be able to undergo reconsolidation
ary conditions and which inhibit reconsolidation from occurring. within the BLA two days after learning. This is exactly what was
The discovery of such molecular signatures would permit strong observed, which indicated that one brain area can inhibit reconsol-
predictions that could unambiguously be addressed experimen- idation from occurring elsewhere. It remains an empirical question
tally; if memory strength, age, or extinction are robust boundary if the hippocampus is the only memory system that can inhibit
conditions, then the putative molecular mechanisms mediating reconsolidation in other systems. Indeed, we might predict that
boundary conditions should be fully expressed under the respec- extinction could form an inhibitory memory trace in hippocam-
tive experimental conditions. Conversely, when a memory does pus or prefrontal cortex which could suppress the induction of
reconsolidate (e.g. after weak training or short retention inter- reconsolidation in amygdala (Mamiya et al., 2009).
vals), then the mechanisms mediating boundary conditions should Given these results by Wang et al., we predicted that stronger
be minimally expressed. This strategy would signicantly comple- auditory fear conditioning might induce a boundary condition on
ment the behavioral studies described above in their search for true reconsolidation by reducing the expression of NR2B subunits in
boundary conditions, and could help resolve some of the conict- the BLA. This decrease is a plausible effect, as the ability of training
ing ndings in the eld. In addition, it could create a framework to differences to affect NMDAR subtype composition has previously
guide future research on boundary conditions by investigators who been described in a study showing decreased NR2B in amygdala
are studying these complex issues. following strong fear conditioning (Zinebi et al., 2003). We thus
predicted that increasing the strength of fear training could lead
3.4. A general principle that could mediate boundary conditions to a corresponding decrease in NR2B expression in the BLA, and
weak training to a small (or no) decrease in NR2B levels (with
One general principle that could mediate boundary conditions all comparisons relative to baseline established by naive animals).
is the down-regulation of mechanisms that allow memories to Behaviorally, these differences in NR2B expression would manifest

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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as different probabilities that a memory would undergo recon- 4. Metaplastic processes as mechanisms of memory
solidation after reactivation. This is exactly what was found. Two stability
days after strong training, a time point when the memory does
not undergo reconsolidation, the levels of the NR2B subunit were Based on the above discussion, it appears that a change in the
reduced by 50%. However, the levels of NR2B subunits were at expression of a destabilization mechanism can prevent the induc-
control levels 60 days after training, a time point when the mem- tion of reconsolidation. However, it has been observed that some
ory does undergo reconsolidation. These ndings were consistent memories can be resistant to reactivation by one procedure but not
with our goal of nding positive molecular evidence to support the another (Lee, 2010; Suzuki et al., 2004; Winters et al., 2009). It is
negative behavioral ndings that dene boundary conditions. likely that certain reactivation procedures can overcome the plas-
All the evidence so far described from this manuscript showed a ticity barriers to reconsolidation in two ways. One possibility is
relationship between reconsolidation and the level of NR2B sub- that different reactivation procedures (novel stimuli, longer reac-
units, but no direct evidence for a functional relationship. One tivation) induce a stronger plasticity induction signal capable of
manner in which Wang and colleagues tested for a functional rela- reaching the experience-induced elevation in threshold for plastic-
tionship between the level of NR2B subunit and reconsolidation ity induction via some plasticity pathway (i.e. NMDAR activation).
was to examine expression of these receptors two days after con- Another is that the suppression of one plasticity mechanism may
ditioning in animals with hippocampus lesions. At that time-point still permit (or even enhance) plasticity induction via another
the strong memories do not undergo reconsolidation. However, mechanism. It is possible that certain reactivation procedures may
pre-training lesions of the dorsal hippocampus were observed to be better suited to engage specic plasticity mechanisms, thus fail-
permit these memories to undergo reconsolidation in the BLA. ure of one reactivation procedure to induce reconsolidation via one
Wang found that the levels of NR2B receptor subunit were at con- plasticity pathway may not rule out destabilization of this memory
trol levels, thus demonstrating a potential functional relationship following a different reactivation procedure via another pathway.
between the presence and absence of the NR2B subunit in our Put differently, in response to different learning conditions, plas-
task. ticity mechanisms could change to alter the reactivation conditions
This metaplastic restriction on the further induction of plastic- that are capable of inducing lability.
ity and reconsolidation might exist to prevent excitotoxicity (Zinebi The change of plasticity characteristics due to past experi-
et al., 2003; Abraham, 2008), and the apparent return of NR2B to ence is a phenomenon referred to as metaplasticity (Abraham,
basal levels could be an amygdala-specic process that permits re- 2008; Abraham and Bear, 1996). This has been extensively stud-
evaluation of intensely fearful stimuli (see Wang and Morris, 2010 ied in vitro and ex vivo, with several impressive demonstrations of
for discussion). In nature few places or stimuli will forever predict how synaptic plasticity or learning can be affected by prior behav-
danger or reward, so it may be adaptive to have a system which ioral experience (i.e. Quinlan et al., 2004; Zelcer et al., 2006). Most
allows an organism to re-evaluate previously established contin- often this involves a priming stimulus or experience which changes
gencies. the threshold and/or direction of subsequent plasticity induction
We feel that these ndings provide a principle to help concep- (see Abraham, 2008). For instance, in an early study (Huang et al.,
tualize our thinking about the conditions that enable or inhibit 1992) demonstrated that activation of NMDARs can raise the stim-
a memory from undergoing reconsolidation. The boundary con- ulation threshold for induction of long-term potentiation (LTP).
ditions are manifested by down-regulation of some mechanism However, when behavioral manipulations have been used they
critical for destabilizing the memory (in the above case, NR2B). typically consist of non-specic or long-lasting manipulations (i.e.
This will in turn allow the memory to be expressed normally and environmental enrichment, sensory deprivation), and are often
remain insensitive to post-reactivation amnesic treatment. To date, studied in developing neurons or organisms (see Abraham, 2008).
the approach of correlating molecular markers for reconsolidation Thus it is not yet apparent whether similar mechanisms mediate
and boundary conditions has only been demonstrated for extinc- the storage of information under typical learning conditions. Here
tion (Mamiya et al., 2009) and strength of training (Wang et al., we speculate on several mechanisms that may respond to expe-
2009). None of the other reported constraints on reconsolidation rience by altering the stimulation necessary to induce subsequent
have met this criterion, therefore suspected boundaries to recon- plasticity, although this list is in no way intended to be exhaustive.
solidation could simply reect reactivation parameters that are As almost no studies have directly tested the relationship between
ineffective. Using a molecular marker such as NR2B downregula- metaplasticity and reconsolidation (see Section 3.4), much of this
tion could help highlight when a specic memory lies beyond a discussion will be derived from studies using electrophysiology and
reconsolidation boundary. molecular methods. Extrapolation of these ndings to the behav-
One important caveat is that the molecular markers of bound- ioral level is clearly problematic, so we present the following mainly
ary conditions may vary depending on the task and brain region of to highlight possible research avenues that could be pursued by
interest. In this way, in addition to NR2B downregulation it may be those looking to investigate how plasticity induction mechanisms
necessary to identify other destabilization mechanisms for other can be altered by learning.
types of memories. Furthermore, it is possible that the plasticity
mechanisms capable of inducing reconsolidation of a given type of 4.1. Altered calcium transmission
memory may change with experience. As will be discussed in detail
in Section 4, training that produces a memory that does not undergo The ow of calcium into the cytoplasm of neurons is believed
reconsolidation following one type of reactivation procedure may to be one of the major initiators of synaptic plasticity (Ghosh and
be able to after a different reactivation procedure by activating a Greenberg, 1995; Magee and Johnston, 1997; Malenka and Bear,
different plasticity pathway. 2004). Therefore it is not surprising that many of the memory
To summarize this section, it is clear that the reactivation cues destabilization mechanisms identied to date directly (NMDARs,
capable of triggering reconsolidation of a given memory can depend VGCCs) or indirectly (CB1-receptors; Suzuki et al., 2008) regulate
on conditions such as its strength and age. Next we will speculate on calcium signaling. It is only logical to assume that alterations to
several other mechanisms that could mediate the stability of strong these sources of calcium (such as reduced expression of NR2B) may
and old memories. We emphasize that these mechanisms may typ- cause changes in the types of stimuli capable of inducing plasticity
ically prevent induction of lability only following some reactivation at a synapse, as well as the types of cellular changes induced during
procedures but not others. plasticity once it is initiated.

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To facilitate understanding we present a greatly simplied and cortex (Quinlan et al., 2004). Importantly, this is approximately
entirely hypothetical example. For illustrative purposes, imagine the amount of time necessary for a rat to acquire an olfactory
a synapse at which the induction of LTP is observed to require discrimination learning rule that accelerates the acquisition of
calcium inux into the post-synaptic cell that is mediated 60% by subsequent pairs of odors (see Saar et al., 2012). Although this rule-
NMDARs and 40% by L-VGCCs (to simplify we have excluded other learning was observed to require NMDAR activity, once the rule is
plasticity mechanisms). Following this potentiation, additional LTP acquired additional odor pairs can be learned in a manner unim-
induction is observed to induce calcium inux that comes 50% from paired by systemic injections of NMDAR antagonist, MK-801. The
each source, likely due to changes in synaptic efcacy or expression change may have been due to a decrease in NR2B expression and
of each membrane protein (i.e. NR2B down-regulation). However, not an increase in NR2A (Lebel et al., 2006). Incredibly, this dis-
beyond this point, the same LTP induction protocol fails to induce crimination learning was also found to signicantly disrupt later
further potentiation. Rather than having saturated the strength of induction of LTP, and application of an NR2B antagonist (ifenprodil)
this synaptic connection, it may be that certain forms of induction was found to impair eld excitatory post-synaptic potentials of
may be prevented. Calcium may still enter via NMDARs, but their naive and pseudo-trained animals signicantly more than trained
contribution may be insufcient to induce further long-term synap- animals (Quinlan et al., 2004). Importantly, it is known that LTP
tic changes via this pattern of stimulation. Initiating additional LTP can be induced similarly in ex vivo slices of trained and untrained
may necessitate an induction procedure that increases calcium animals when higher stimulation frequency is used (Lebel et al.,
inux via other sources, which, in regards to behavioral proce- 2001). Thus rule-learning apparently increases the threshold for
dures, might translate to a rather different reactivation protocol. LTP induction, and might not be due merely to LTP saturation or
From in vitro work it has been noted that NMDAR-dependent and occlusion by training-induced increases in synaptic transmission
L-VGCC-dependent LTP can rely on different induction procedures (as observed by Saar et al., 1999, 2002). Together this work indi-
(Grover and Teyler, 1990), with signal-transduction pathways that cates that NR2B down-regulation during learning may interfere
can be functionally independent (Cavus and Teyler, 1996; Huber with subsequent plasticity induction in a manner that resembles
et al., 1995). In the following sections we will propose that during metaplasticity (Abraham and Bear, 1996).
learning a similar transition could occur among the many plasticity
induction mechanisms (including NMDARs, calcium-permeable - 4.1.1.2. NMDAR trafcking as a metaplasticity mechanism. Seminal
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors work on the topic of experience-dependent NMDAR trafcking
[CP-AMPARs], and L-VGCCs) at memory-encoding synapses. The revealed differential regulation of these receptor subunits dur-
implication of such metaplastic changes is that different train- ing development (X.-B. Liu et al., 2004; Sheng et al., 1994). In
ing procedures will produce memories with different sensitivities immature visual cortex, NR2Bs are in abundance but are rapidly
to specic reactivation procedures, as observed for some of the down-regulated at the closure of a critical sensitive period of
boundary conditions discussed in Section 3. In the following we enhanced plasticity that occurs shortly after newborn animals open
will discuss some examples that could mediate such a switch. their eyes (Carmignoto and Vicini, 1992). Limiting visual input by
raising animals in darkness can postpone this shift in relative sub-
4.1.1. NMDA-receptors unit levels and extend the sensitive period, but even brief (12 h)
We have already discussed how post-synaptic expression of exposure to light has been observed to cause the NR2B:NR2A ratio
NR2B-subunits might serve as a mechanism to gate memory to rapidly decrease along with immediate termination of the crit-
destabilization. In brief, we expect that as learning approaches ical period (Philpot et al., 2001b; Quinlan et al., 1999). As this
asymptote, NR2Bs in relevant cortical or amygdala synapses should period is thought to be necessary for the establishment of funda-
be downregulated to prevent these connections from entering a mental visual system properties including orientation selectivity
labile state during future events. and ocular dominance columns (Hensch, 2005; Karmarkar and
Dan, 2006), changing NMDAR composition could help cement this
4.1.1.1. Changes in expression of NR2A and NR2B in response to expe- crucial activity-dependent remodeling and prevent it from under-
rience. Each NMDAR is a heterotetramer typically comprising two going decay or interference during subsequent experience. Similar
NR1 receptor subunits, and two other subunits. In the mature fore- experience-dependent transitions have been observed for other
brain of rodents these are thought to be primarily NR1NR2A, brain regions and species (Bellone and Nicoll, 2007; Singh et al.,
NR1NR2B, and NR1NR2ANR2B containing receptors (L. Liu et al., 2000), suggesting that this may be a fundamental mechanism of
2004; Luo et al., 1997), but from the above discussion it is clear that synaptic stability.
the rate of expression of each can change. Indeed, the expression For example, in the developing hippocampus LTP can very
and trafcking of each subtype seem to be regulated indepen- rapidly (within seconds) increase the NR2A:NR2B ratio a pro-
dently (see Lau and Zukin, 2007 for a review). In the study by cess which can be reversed by depotentiation (Bellone and Nicoll,
Wang et al. (2009) discussed previously, strong training specically 2007). Interestingly, hippocampal NR2A-overexpression is known
reduced NR2B expression for at least two days without signicantly to reduce LTP magnitude (Barria and Malinow, 2005). Similarly,
altering NR1 levels. When auditory fear conditioning consisted of in song-mimicking Zebra nches, abrupt NR2B down-regulation
one toneshock pairing with nine unsignaled footshocks, NR2B is exhibited alongside dramatic remodeling of cortices (such as
levels in BLA were still reduced though reconsolidation of the audi- the lateral magnocellular nucleus of the anterior neostriatum
tory memory could still be induced. One interpretation is that the [lMAN]) during critical periods for song learning (Singh et al.,
reduced NR2B levels in this control group could have been involved 2000). Isolation from the songs of conspecics, which is required
in maintaining a strong contextual fear memory, though this was for song learning, both delays this critical period and selectively
not empirically tested. increases NR2B mRNA within lMAN. Although these changes in
Similar work by Zinebi et al. (2003) has previously demon- NMDAR-composition are each developmentally regulated, they
strated that rats given very strong auditory fear conditioning (20 are also experience-dependent, thus they potentially provide an
toneshock pairings) exhibit reduced NR2A and NR2B levels rel- exaggerated demonstration of what can occur during other types
ative to unpaired and naive control animals, though NR2Bs in of learning throughout the brain. Importantly, even long after
particular were more strongly down-regulated (Zinebi et al., 2003). the termination of critical periods there are forms of behavioral
Relatedly, after six days of training at an odor discrimination task, experience (such as prolonged visual deprivation) that have been
the NR2A:NR2B ratio has been observed to increase in the piriform observed to re-engage widespread cortical remodeling in adult

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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rodents (Montey and Quinlan, 2011; Philpot et al., 2001b), which of auditory tone and footshock should have strongly identied
supports our position that even the strongest and oldest memories the predictive, co-occurring stimuli (CS and US), thus consider-
may not be entirely invulnerable to modication. able change in the NR2A:NR2B ratio should confer stability against
additional plasticity induction during reactivation (Wang et al.,
4.1.1.3. NR2A:NR2B ratio dictates the stimulation that induces bidi- 2009). Importantly, this NR2B down-regulation may be at least
rectional plasticity?. This switch in subunit expression may alter functionally specic, as animals given one toneshock pairing plus
plasticity induction for several reasons. These subunits have dif- nine unsignaled shocks also exhibited comparable NR2B down-
ferent current transmission characteristics, partly due to the lower regulation (perhaps involved in preserving contextual predictors
glutamate afnity and faster desensitization of NR2As (Cull-Candy of shock), yet their auditory fear memory was still able to undergo
and Leszkiewicz, 2004; Monyer et al., 1994; Vicini et al., 1998). reconsolidation. However, stimuli that were once dangerous may
NR2B subunits also typically carry more calcium charge per unit not always be so, thus the neurophysiology of the amygdala may
than NR2A (Erreger et al., 2005; Massey et al., 2004; Sobczyk allow this change in NMDAR composition to reset, which could
et al., 2005), exhibit less calcium-induced desensitization, and have allow formerly fearful stimuli to be re-evaluated over time in an
slower channel kinetics, but also a lower open probability (see Lau adaptive manner (see Wang and Morris, 2010 for discussion). A
and Zukin, 2007). Finally, the important plasticity kinase, CaMKII, similar property may not exist for cortical regions, as without
may bind preferentially to NR2B subunits (Barria and Malinow, experimental manipulation the NR2B:NR2A ratio might remain low
2005; Mayadevi et al., 2002). Perhaps because of this tethering, after developmental plasticity periods (see Sheng et al., 1994).
calcium inux via NR2B-containing NMDARs has been observed to
selectively induce autophosphorylation of CaMKII under some con- 4.1.1.4. NR2Bs may mediate spine growth and remodeling?. Not
ditions (Bayer et al., 2001; Strack and Colbran, 1998; Strack et al., only might the activity-dependent switch in NMDAR composi-
2000). Activation of CaMKII in this manner is thought to be neces- tion change bidirectional plasticity thresholds, but it could also
sary for many forms of long-lasting synaptic change (Lisman et al., alter the types of structural changes induced during plasticity. For
2002; Zhou et al., 2007). The cytoplasmic tail of each subunit may example, NR2Bs may permit substantial neuronal remodeling, such
selectively confer the ability to interact with synaptic scaffolding as dendritic growth/retraction and spine expansion, while NR2As
and signaling proteins including CaMKII. It has been demonstrated may allow only for more subtle alterations of synaptic structure
that the NR2B C-terminus itself may promote the induction of plas- by tuning the strength of existing synaptic connections (Ewald
ticity (LTP), while the NR2A tail may actively prevent it, in a manner et al., 2008; Gambrill and Barria, 2011; Lee et al., 2010; Peng
that was unaffected by point-mutation of the NR2A PSD-95 bind- et al., 2010; Sepulveda et al., 2010; Zhang et al., 2009). This is
ing site and independent of the differential capacity for calcium supported by the observation that NR2Bs may allow for increased
transmission (Foster et al., 2010). In this way, the calcium transmis- spine and lopodia motility, suggesting their role in the estab-
sion capacity of each subtype may under some conditions be less lishment or removal of synaptic connections, while NR2As may
critical than the plasticity pathways each can trigger via protein work to stabilize existing neuronal structure (Gambrill and Barria,
interactions at the C-tails. 2011). In hippocampus, silencing of individual synapses has been
Rather than preventing plasticity induction entirely, consider- observed to selectively increase NR2B:NR2A ratio, and decrease the
able evidence suggests that changes to NMDAR composition are threshold for LTP induction (Lee et al., 2010). Amazingly, in this
likely to change the forms of activity that can induce bidirec- study even weak, sub-threshold stimulation of a synapse (via glu-
tional plasticity. Because of their higher glutamate afnity and tamate uncaging) could cause spine growth, but only at silenced
slower decay kinetics, NR2Bs allow for greater temporal summa- synapses with elevated NR2B. This supports the position that NR2Bs
tion of calcium currents than do NR2As, which require a more may be particularly important for the establishment of functional
rapid stimulation rate to reach plasticity thresholds (Philpot et al., synapses. Given appropriate activity (in the case of ocular domi-
2001a, 2007). Essentially, the maximum time between depolar- nance columns in adults, this requires chronic visual deprivation),
ization and glutamate stimulation at the NMDAR that permits widespread plasticity may still be possible in synapses with high
calcium transmission is longer for NR2Bs than NR2As, so the coinci- NR2A:NR2B ratios, though this might rely on insertion of NR2Bs
dence detection ability ascribed to NMDARs could be shortened as (He et al., 2006), perhaps into perisynaptic or extrasynaptic regions
NR2A:NR2B ratio increases. Additionally, an increased NR2A:NR2B (Yashiro et al., 2005) without altering synaptic composition (see
ratio appears to switch the types of plasticity that can be induced Kopp et al., 2007). In this way, synaptic structure could be largely
by NMDAR activity. This could occur as a shift in plasticity thresh- maintained following developmental NR2A up-regulation.
olds, such that long-term depression (LTD)-like changes become These distinct forms of structural plasticity might help explain
more readily inducible than LTP (Bear, 1995; Bienenstock et al., phenomena like the transience of conditioned fear extinction
1982; Philpot et al., 2001b, 2003; Quinlan et al., 1999; Xu et al., (Bouton, 2004). Under some conditions, extinction may induce
2009). Philpot et al. (2007) proposed that the switch from NR2B depotentiation of amygdala synapses that were strengthened dur-
to NR2A might occur primarily in response to increased activity, ing fear conditioning (Kim et al., 2007). However, it is widely
leading to an increased threshold of stimulation frequency neces- understood that extinction establishes a new inhibitory mem-
sary for LTP. While LTP in all cases may require NR2As (Philpot ory trace, without permanently modifying the original training
et al., 2007), when NR2Bs are down-regulated the induction of fur- memory (Bouton, 2004). It is conceivable that due to elevated
ther LTP becomes increasingly difcult (Kirkwood et al., 1995). This NR2A:NR2B ratio in amygdala, extinction may be mediated by
may cause only highly correlated inputs to a neuron to trigger the changes to synaptic strength without dramatically altering synap-
molecular coincidence detection system supported by NMDARs. tic connections or inducing extensive remodeling of synapses. In
Thus, one function of increasing NR2A expression may be to tune this way, the synaptic strength may be decreased by extinction,
memory encoding such that only the synapses which encode reli- but the retention of connections established during conditioning
ably co-occurring inputs may persist (see Bienenstock et al., 1982 may allow this fear response to recover over time or during rein-
for a relevant model). statement procedures. Again, this does not mean that NR2Bs are not
This sits well with our conceptualization of reconsolidation, as involved in fact, amygdala NR2Bs appear necessary for fear extinc-
both models propose that strongly correlated (predictive) sensory tion (Sotres-Bayon et al., 2007) but a reduction in their expression
inputs should be strengthened while others might be lost. Thus during strong training could alter the forms of plasticity induced by
it might be concluded that overtrained animals given 10 pairings extinction. This also raises the possibility that in the study by Wang

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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et al. (2009), NR2B subunits are necessary to induce spine motility. NMDAR activity was inhibited. Although Clem and colleagues saw
NR2A might still permit plasticity during reactivation, though this no evidence of altered NR2A:NR2B ratio after their task (they sug-
may not cause signicant remodeling of synaptic connections. It is gested that the inhibitory inuence of NMDARs could instead be
possible that gross, NR2B-dependent synaptic remodeling may be mediated by altered signaling cascades), this work indicates that
necessary to render the memory vulnerable to protein synthesis after extensive training NMDAR activity could actually prevent
inhibition. additional plasticity. This might be related to the LTP-suppressing
effects of the NR2A C-tail discussed above (Foster et al., 2010).
4.1.1.5. Summary: differential regulation of NMDAR-subunits helps Increasing the expression of NR2A relative to NR2B C-tails at the
stabilize synapses. It is difcult to draw a clear conclusion from this synapse may thus also restrict plasticity.
metaplasticity literature when even the basic physiological prop- In conclusion, we expect that these characteristics of NR2B
erties, such as the involvement of NR2A and NR2B in LTP, remain expression may confer reduced stimulation selectivity of a synapse
quite contested (see Lee et al., 2010; Massey et al., 2004; Yashiro to undergo plasticity. This means that if NR2A:NR2B ratio is ele-
and Philpot, 2008). Perhaps the interpretation that best ts the vated following strong training, the likelihood that a subsequent
data reviewed here is that NR2Bs can elevate the sensitivity and experience will induce plasticity at the memory-encoding synapses
reduce the selectivity of neuronal networks to encode new infor- will be reduced. At the extreme, this mechanism apparently pre-
mation. Their characteristics might endow synapses with the ability vents memory destabilization (Wang et al., 2009). However, we
to encode weaker and more temporally separated inputs. A simple suspect that for most memories it should be possible to induce
model might predict that as encoding of a task approaches asymp- reconsolidation using different reactivation protocols (that perhaps
tote, an elevated NR2A:NR2B ratio may require increasingly strong recruit plasticity mechanisms other than NMDARs, such as calcium-
or correlated pre- and post-synaptic activation to trigger additional permeable AMPARs, mGluRs, or L-VGCCs). For instance, perhaps
synaptic strengthening, due to the fast kinetics and lower per-unit inating the incentive or aversive value of an unconditioned stim-
calcium current of NR2As (Erreger et al., 2005; Sobczyk et al., 2005). ulus might release additional neuromodulators (see Wise, 2004),
Thus, it might be imagined that an increasing NR2A:NR2B ratio which could boost the plasticity signal and thus reactivate an oth-
as information is encoded might make it less likely that any sub- erwise stable memory (see Wang et al., 2005 for relevant ndings).
sequent stimulation (as evoked by behavioral experience) would This position might help explain why well trained drug memories
reactivate a synapse by inducing further potentiation. Increasing might continue to undergo reconsolidation (Milton et al., 2008a),
relative levels of NR2A at the connections of a memory-encoding as one theory proposes that repeated drug-taking should progres-
neuronal ensemble would thus tune each synapse toward par- sively sensitize their incentive value (Robinson and Berridge, 2008).
ticular inputs. Those synapses that happen to be strongly and However, we surmise that at extremely high NR2A:NR2B ratios,
consistently activated during subsequent experience may persist, induction of additional potentiation may be all but impossible,
as their elevated NR2A:NR2B ratio might make it very unlikely that thus altering this memory may require the induction of synap-
further stimulation could reach the elevated threshold for addi- tic depotentiation- or depression-like changes. In sensory cortices
tional potentiation. Applied to memory processing, incremental such processes may only be engaged in highly stable memories (like
training of a task might gradually increase NR2A:NR2B ratio until it ocular dominance columns) by chronic experience (like monocu-
can no longer reach the threshold for plasticity. Unrelated behav- lar sensory deprivation; see He et al., 2006). Such weakening of
ioral experiences are very unlikely to engage plasticity in this strong potentiated synapses could be dependent on NR2As (Cho et al.,
circuit because they do not have strong enough inputs. Instead 2009; Massey et al., 2004), calcium-permeable AMPARs (Yang et al.,
unrelated tasks should recruit other circuits with lower NR2A:NR2B 2010), and/or mGluRs (Wu et al., 2004). In reference to the ndings
ratio, and thus an elevated sensitivity for plasticity induction. This of Wang et al. (2009), perhaps a form of homeostatic synaptic scal-
should prevent interference. ing (see Prez-Otano and Ehlers, 2005) could gradually relieve the
Those connections that are only weakly potentiated by an expe- barriers to reconsolidation over weeks.
rience may express a lower NR2A:NR2B ratio, which may leave
the information they encode vulnerable to interference or decay 4.1.2. L-type voltage-gated calcium channels (L-VGCCs)
by subsequent activation of NMDARs (see Quinlan et al., 2004 for Given the aforementioned role of hippocampal L-VGCCs in
a related discussion). In this way, a low NR2A:NR2B ratio could destabilizing memory following reactivation (Kim et al., 2011;
maintain storage capacity by permitting the elimination of weakly Suzuki et al., 2008), it might be expected that the barriers
encoded information via an active decay process (whereby mem- to reconsolidation observed for hippocampus-dependent tasks
ories that are not strongly encoded are overwritten by newer (Morris et al., 2006; Suzuki et al., 2004) could be mediated by
experiences; see Izquierdo et al., 1999; Xu et al., 1998). Consis- a down-regulation of these channels in a manner similar to the
tent with this position, decay of both LTP and weak radial arm down-regulation of NR2B subunits in amygdala following strong
maze memory over six days can be prevented by daily injections of training (Wang et al., 2009). However, in this section we will discuss
NMDAR antagonist, CPP (Villarreal et al., 2002). Under some con- the possibility that L-VGCC activity in hippocampus and elsewhere
ditions an increased NR2A:NR2B ratio appears to reduce overall might actually transiently facilitated following some types of learn-
NMDAR transmission (i.e. Lee et al., 2010), which could function in ing, as neuronal activity in response to stimulation is increased
an analogous manner to prevent decay. due to enhanced synaptic strength. We propose that this may actu-
Altered NMDAR properties following experience may not only ally facilitate the induction of reconsolidation of some tasks shortly
reduce the calcium signal induced by stimulation. They may also after their acquisition. Although there are several types of neuronal
suppress potentiation mediated by other plasticity mechanisms. L-VGCCs, two that will be specically discussed in this review are
For example, NMDARs were necessary for repeated single whisker encoded by the pore-forming CaV 1.2 and CaV 1.3 subunits.
stimulation to strengthen in vivo potentiation of layer 4 to 2/3
synapses in barrel cortex (Clem et al., 2008). But once synapses were 4.1.2.1. Experience-dependent changes in L-VGCC expression?.
strongly potentiated, NMDARs were actually observed to suppress While L-VGCCs have often been linked to processes like home-
further synaptic strengthening, as application of an NMDAR antag- ostatic plasticity and metaplasticity (Thiagarajan et al., 2007;
onist permitted additional LTP. Activation of group I metabotropic Wankerl et al., 2010), their regulation is not well dened, with
glutamate receptors (mGluRs) was necessary to induce additional some suggesting that their expression and/or activity might be
strengthening of these potentiated synapses when the suppressing altered by experience (see Oh et al., 2010), and others reporting

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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less evidence for activity-dependent expression changes (Di Biase that do not reach ring threshold, and thus when action poten-
et al., 2011). A majority of these channels seem to form stable tials are not induced (Mermelstein et al., 2000; Yasuda et al., 2003).
complexes at the cell membrane of dendrites, along with 2- Furthermore, other mechanisms (such as noradrenergic activity)
adrenergic receptors, CaMKII, calcineurin, protein kinase A (PKA), might counteract the direct activation of potassium channels by
A-kinase anchor protein 79 (AKAP79/150), and calmodulin (Davare calcium (Foehring et al., 1989), which under some conditions could
et al., 2001; Oliveria et al., 2007; Zhlke et al., 1999), while a small maintain or even increase excitability (see Section 4.2) and further
minority (approximately 20%) may be unitary and motile (Di Biase promote L-VGCC activity during learning.
et al., 2011). At basal activity levels these receptors appear to have The endocannadinoid CB1 receptor is necessary for destabiliza-
turnover rates, and even some binding partners, which are similar tion of hippocampus-dependent memories following reactivation
to the rather stable NMDARs (see Di Biase et al., 2011). (Suzuki et al., 2008; Kim et al., 2011), and could also inuence
In young neurons, long-lasting depolarization and NMDAR acti- neuronal and L-VGCC activity. As CB1 receptors are implicated
vation are each known to reduce calcium currents via L-VGCCs and in the regulation of inhibitory GABAergic neurons in the hip-
to induce their endocytosis (Green et al., 2007), though this may pocampus (Diana and Marty, 2004; Wilson and Nicoll, 2001), one
not occur in mature neurons (Di Biase et al., 2011). In a related possibility is that CB1 activation during depolarization can actu-
study, strong activation of L-VGCCs, though not NMDARs, was ally briey suppress inhibitory connections to pyramidal neurons.
found to cause depression of R-type VGCCs (Yasuda et al., 2003). Strikingly, it has been found that CB1s, which can be activated
The authors of these studies have suggested that this suppression when stimulated pyramidal neurons release endocannabinoids
of VGCCs might function to prevent excitotoxicity due to excessive (Chevaleyre and Castillo, 2003), are necessary to induce several
calcium inux. However, it is not clear if this mechanism might forms of inhibitory suppression in hippocampus, which can facil-
also be recruited to support memory stability. Opposing this pos- itate subsequent LTP induction in this structure (Carlson et al.,
sibility, several studies have found only a very brief inhibition of 2002; Chevaleyre and Castillo, 2004). One possibility is that by dis-
L-VGCCs in response to very strong stimulation (Budde et al., 2002; inhibiting neurons that encode a given memory, this metaplastic
Imredy and Yue, 1994), which would be unlikely to affect meta- mechanism could also increase their activity and enhance L-VGCC-
plasticity across multiple behavioral experiences. However, some mediated calcium inux during strong activation.
unpublished results have indicated that in adult rats, the success- Due to the partners with which they interact or bind into macro-
ful acquisition of a hippocampus dependent task, trace eye-blink molecular complexes, L-VGCCs are also in a position to have their
conditioning, is associated with reduced expression of L-VGCCs in activity modied by other mechanisms engaged during neuronal
CA1 (see Nunez-Santana et al., 2009 and Oh et al., 2008 in Oh et al., activity or memory reactivation (Calin-Jageman and Lee, 2008). It
2010). This work might implicate the regulation of L-VGCC expres- is known that as neuronal stimulation is increased, L-VGCC activ-
sion as a mechanism of metaplasticity. However, it is complicated ity can be facilitated via PKA phosphorylation (Sculptoreanu et al.,
by the nding that in hippocampus neurons, strong depolarization 1995). Activity of phosphorylated L-VGCC isoform CaV 1.2 can also
might also increase L-VGCC trafcking to distal dendrites (Wang exhibit dramatic voltage-dependent facilitation when a depolariza-
et al., 2007). Evidently much more work is needed to determine tion occurs just prior to stimulation (a characteristic of spike-timing
whether expression of L-VGCCs may be regulated by experience in dependent plasticity, Bourinet et al., 1994). Interestingly, it has
a manner similar to NMDARs, although it presently seems unlikely. been suggested that L-VGCC phosphorylation (likely by PKA) can
also prevent calcium-evoked inactivation of these channels in neu-
4.1.2.2. Regulation of L-VGCC activity. Even if membrane expres- rons (Budde et al., 2002), which could allow for their prolonged
sion of L-VGCCs does not change substantially due to experience, activation. In cardiac preparations, CaMKII can target to L-VGCCs
this does not rule out their involvement in altering the reactivation when activated by calcium, where it remains persistently tethered
requirements necessary for reconsolidation. These channels are, as even after calcium levels decrease (Hudmon et al., 2005). How-
their name indicates, voltage-sensitive. Some studies have reported ever, the activity of CaMKII remains calcium-dependent, which
that the number of VGCCs (or VGCC clusters) are somewhat evenly works as a metaplastic mechanism to facilitate L-VGCC activity
distributed in the cellular membrane of dendritic shafts and spines in both an experience- and activity-dependent manner. It is not
(see Di Biase et al., 2008; Obermair et al., 2004), and the density in clear if a similar relationship with CaMKII exists for neuronal L-
dendritic spines may remain proportional to their size, thus keeping VGCCs (though see Person and Raman, 2010 for related ndings
cytosolic accumulation of calcium per action potential somewhat from cerebellum). Relatedly, it has been claimed that activity of
constant (Sabatini and Svoboda, 2000). However, the frequency of neuronal CaV 1.3 channels may increase during intense depolariz-
action potentials and the total time that a neuron spends in a depo- ing stimulation due to calcium-dependent facilitation (CDF) via an
larized state during stimulation might be expected to increase with interaction with CaMKII and a post-synaptic density protein, densin
synapse strength. Independent of all other factors this would be (Jenkins et al., 2010). Adrenergic activity at 2-receptors has also
expected to increase calcium inux and accumulation via L-VGCCs been found to increase activity of L-VGCCs in hippocampus, pos-
in response to a given excitatory input. sibly via phosphorylation by PKA (Hoogland and Saggau, 2004;
Counteracting this increased calcium inux via L-VGCCs, activa- Gray and Johnston, 1987). Furthermore, activation of glucocorti-
tion of calcium-sensitive potassium channels may tend to decrease coid receptors with corticosterone may cause a dramatic increase
neuronal excitability during increased calcium inux via L-VGCCs, in membrane expression of L-VGCCs (Chameau et al., 2007). In this
thus reducing cell ring rate (Marrion and Tavalin, 1998). But way, stress and arousal induced during retrieval might also increase
recent evidence indicates that only the CaV 1.3 isoform controls an calcium inux via L-VGCCs, in addition to their enhanced activ-
important component of neuronal excitability (slow after hyperpo- ity due directly to voltage elevations. From this interpretation one
larization [sAHP]), thus changes in CaV 1.2 activity due to increased might expect that emotional tasks, such as aversive and appetitive
neuronal activation may have little direct impact on this aspect of conditioning, might be more likely to increase L-VGCC expression
cell ring rate (Gamelli et al., 2011). Some neuronal L-VGCCs (likely due to elevated release of these hormones (i.e. Cordero et al., 2003).
CaV 1.3) may be designed to respond to weaker electrical depolar- It is not just possible to facilitate L-VGCCs; rather they can
ization (Avery and Johnston, 1996; Lipscombe et al., 2004; Magee be bidirectionally modied. It is well established that both
et al., 1996) within large dendritic regions (Rabinowitch and Segev, calcium-dependent facilitation and inactivation can occur through
2006; Thiagarajan et al., 2007). Specically, some L-VGCCs may L-VGCC-bound calmodulin (see Budde et al., 2002 for review).
be preferentially activated during longer periods of depolarization In fact it has been reported that calcium-induced activation of

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and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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calmodulin that is bound to L-VGCCs can exert either a facilita- are most effective (Rabinowitch and Segev, 2008), which could
tory or an inhibitory effect on channel activity, depending on the help extract the strongest input patterns to a cell in order to drive
number of calcium ions bound (Zhlke et al., 1999). In mammalian optimal output and maximize encoding capacity. This could relate
kidney and hippocampus cells, it was conrmed that PKA can to synaptic cross-capture experiments, in which plasticity-related
strongly enhance L-VGCC activity, but calcineurin binding to the L- products synthesized by strong LTP at one synapse can be captured
VGCC protein complex (including AKAP79/150 and calmodulin) can to promote LTD at nearby synapses, and vice versa (Sajikumar and
powerfully suppress this enhancement (Oliveria et al., 2007). These Frey, 2004). In this way, strength of synapses where activity is most
authors proposed that either weaker or prolonged depolarization highly correlated with neuronal ring may be enhanced, and con-
may escape inhibition by calcineurin and encourage facilitation via nections that are not as highly correlated will be weakened until
PKA. only the optimal inputs remain potentiated. This may be one low-
We argue that together, these protein interactions and kinetic level L-VGCC-mediated process by which the brain can identify
properties of L-VGCCs should increase their calcium transmission the predictive cues from experience and reduce the inuence that
as synaptic response to stimulation increases due to enhanced unpredictive cues will have on behavior. Homeostatic processes
synaptic strength. As encoding of some tasks in some brain regions would also tend to bring elevated rates of cellular activity back
is thought to be mediated at least partially by synaptic potenti- toward basal levels (see Turrigiano, 2008), suggesting that L-VGCC
ation (Bliss and Collingridge, 1993; Maren, 1999; Rioult-Pedotti activity may at rst be increased, but may then gradually decrease
et al., 2000; Whitlock et al., 2006; though also see Braunewell and as homeostatic changes balance overall neuronal activity levels. On
Manahan-Vaughan, 2001), potentiated memory-encoding neurons its own this transition over time could be expected to reduce the
may exhibit enhanced calcium inux via these channels during likelihood of L-VGCC-dependent plasticity.
reactivation relative to the inux they mediated during initial Because of these properties, VGCCs likely respond to very differ-
learning. Once beyond a potentiation or stimulation threshold, ent stimulation patterns than NMDARs (Bauer et al., 2002; Cavus
voltage- or calcium-dependent inactivation may function to limit and Teyler, 1996; Grover and Teyler, 1990; S.-J.R. Lee et al., 2009; Li
further increases in L-VGCC activity. As will be discussed below, and Burrell, 2011; Magee and Johnston, 1997), and once activated
homeostatic processes might scale down the strength of nearby they might induce very different signaling pathways (Oliveria et al.,
synapses on neurons with potentiated connections (Turrigiano, 2007; Tsui and Malenka, 2006; Yasuda et al., 2003). As an example,
2008), thus over time a decrease in L-VGCC activity should also be in one amygdala electrophysiology study it has been demon-
observed. One behavioral consequence of such changes to L-VGCC strated that NMDAR-dependent LTP is induced by long-lasting
activity could be that weakly and recently acquired memories may post-synaptic depolarization evoked by tetanic stimulation, but L-
be more sensitive to L-VGCC-mediated destabilization, which could VGCC-dependent LTP is induced by weak presynaptic stimulation
be the case in the study by Suzuki et al. (2004) and others. Of course administered with strong, spike-evoking postsynaptic depolariza-
this is just one tenuous explanation of these results, and many other tion (Bauer et al., 2002). This would predict that a suppression
mechanisms could account for the observed resistance of older and of NMDAR activity, such as occurs during experience-dependent
stronger memories to undergo reconsolidation. NR2B down-regulation, should make it less likely that certain stim-
ulation patterns will induce plasticity. However, those patterns that
4.1.2.3. Involvement of L-VGCCs in plasticity. But how might an activate L-VGCCs may remain, or could potentially be enhanced as
altered calcium signal via L-VGCCs inuence plasticity? Although synaptic strength is increased by experience. By generous exten-
calcium inux through these channels might allow the ef- sion of these principles, one might surmise that different behavioral
cacy of individual synapses to be selectively increased via reactivation protocols might evoke input patterns to a neuron that
back-propagation of action potentials to active spines (Magee could preferentially engage one plasticity mechanism or another
and Johnston, 1997), regenerative local spikes (Golding et al., based on the stimulation tuning of each. We will not attempt to
2002), or very localized activation of calcium substrates within speculate on what sorts of behavioral experiences might engage
microdomains around each channel (S.-J.R. Lee et al., 2009; Rose one plasticity mechanism or the other. But we imagine that the
et al., 2009; Tsui and Malenka, 2006; Yasuda et al., 2003), L-VGCCs establishment of synaptic connections and/or tags during prior
might function primarily to alter the strength of multiple synapses experience may permit L-VGCC-mediated plasticity products to
in response to more global changes in cellular activity. In fact, some target to these specic synapses, perhaps even in the absence of
have reported that they contribute little to spine calcium accu- additional NMDAR activity (Ishikawa et al., 2008). This principle,
mulation during action potential ring (Yasuda et al., 2003), and known as synaptic tag-and-capture (Frey and Morris, 1997), could
instead may be involved primarily in activating nuclear signaling potentially allow L-VGCCs activated in the proximal dendrites or
pathways required for gene transcription as a result of depotentia- cell body during synaptic stimulation to mediate plasticity pro-
tion of large dendritic regions (Deisseroth et al., 1998; Graef et al., cesses specically at the activated connection(s).
1999; Mermelstein et al., 2000; Oliveria et al., 2007; West et al., After their activation, L-VGCCs and NMDARs may also under-
2002). lie subtly different protein cascades for inducing plasticity (Cavus
Due to these properties it has been proposed that L-VGCCs might and Teyler, 1996; Morgan and Teyler, 1999), which can be at least
serve to integrate signals from multiple synapses and inuence het- partially independent, as saturation of LTP via one pathway does
erosynaptic plasticity. For example, it has been suggested that this not occlude the other (Huber et al., 1995). Before proceeding we
may allow L-VGCCs to mediate homeostatic processes like synaptic should again note that NMDARs and L-VGCCs have not been impli-
scaling (Goold and Nicoll, 2010; Rose et al., 2009; Thiagarajan et al., cated in memory destabilization within the same brain regions, but
2007), wherein changes in strength at one synapse may be offset we expect that they could interact to mediate different aspects
by an opposite change of efcacy at all synapses within a dendritic of plasticity. As one example of their specic molecular effects,
region, so as to maintain total neuronal excitation within an opti- calcium inux via NMDARs and L-VGCCs can each trigger CaMKII
mal range (Liu and Tsien, 1995; Losonczy et al., 2008; Turrigiano activation, but the phosphorylation substrates of CaMKII may be
et al., 1998). This could improve the signal to noise ratio, and, due limited by the source of calcium (Tsui and Malenka, 2006). Only
to the maintenance of relative strengths between synapses, could NMDAR-activated CaMKII was observed to phosphorylate stargazin
potentially increase the maximal range of synaptic strengthening and PSD-95, which are processes important for synaptic trafcking
by heterosynaptically lowering baseline ring. It might even be and stabilization of AMPARs (Chen et al., 2000; Kessels et al., 2009).
capable of selecting which patterns of heterosynaptic potentiation However, L-VGCC-activated CaMKII may have been prevented from

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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phosphorylating these targets due to co-activation of calcineurin 2010). It is possible that cocaine re-exposure could induce a similar
or structural constraints. Indeed, in cultured hippocampal neurons, process in NAc.
calcineurin has been reported to be activated only by calcium inux
via L-VGCCs, and may be involved in activating proteins involved 4.1.2.5. L-VGCC summary: a model of memory stability. Together
in plasticity, like the transcription factor NFATc4 (Graef et al., 1999; this work might indicate that rather than inhibiting reconsolida-
Oliveria et al., 2007). Again it is worth noting that CaMKII acti- tion via down-regulation of L-VGCCs, increasing activity of L-VGCCs
vated by NMDAR- or L-VGCC-mediated calcium inux can activate as learning increases synaptic strength may tend to facilitate post-
the proteasome and induce its translocation to the cell membrane reactivation plasticity, even despite the addition of barriers to its
(Bingol et al., 2010; Djakovic et al., 2009). induction such as NR2B down-regulation (Bellone and Nicoll, 2007;
Lee et al., 2010). One speculative possibility is that NMDAR activity
during learning (such as contextual fear conditioning) is necessary
4.1.2.4. Functions of L-VGCCs in learning and memory. As both pro- not just to establish a memory (Bast et al., 2003; Kim et al., 1992),
tein degradation by the proteasome pathway and calcineurin have but to destabilize the existing hippocampal synapses recruited to
been implicated in memory destabilization (Lee et al., 2008; Kim encode this novel task. It appears that L-VGCCs are critical dur-
et al., unpublished observations), it is possible that L-VGCCs might ing consolidation (McKinney and Murphy, 2006; Woodside et al.,
activate these mechanisms during some instances of reconsolida- 2004), perhaps to induce gene transcription (Graef et al., 1999;
tion. This is not meant to imply that L-VGCCs are not involved in Zhang et al., 2006) necessary for long-term memory (see West
learning of new tasks (Borroni et al., 2000; McKinney et al., 2008; et al., 2002). However, once the synapses have been strength-
McKinney and Murphy, 2006), but based on the model presented ened by learning and NR2B subunits have been down-regulated
here it is possible that L-VGCCs could play an increasingly critical (as observed in vitro by Bellone and Nicoll, 2007; Lee et al., 2010,
role in plasticity as circuits are strengthened by learning. Support- see Section 4.1.1), L-VGCCs may become more important for desta-
ing this prediction, in the hands of Suzuki and colleagues L-VGCC bilization at these synapses (Suzuki et al., 2004, 2008). Only beyond
activity was not necessary for contextual fear acquisition (2004), a certain threshold of cellular activity or calcium inux might
but it was required for destabilization of consolidated memories, L-VGCCs engage a negative feedback loop via calmodulin or cal-
though not for their restabilization (2008). This role in destabiliza- cineurin activation (Oliveria et al., 2007; Zhlke et al., 1999), which
tion was also observed for a watermaze task (Kim et al., 2011). could inhibit plasticity. Thus, experience may enhance L-VGCC
Relatedly, in one study it was found that acquisition of a discrim- activity, but beyond a degree of potentiation this mechanism might
inatory visible-platform watermaze task appeared to be normal be suppressed. Over time, learning-induced increases in synaptic
following the rst day of training in L-VGCC subtype CaV 1.2 knock- strength (and thus responding during stimulation) may be par-
out mice, but was impaired on subsequent days of training relative tially offset by synaptic scaling or decreasing cellular excitability
to wild-type mice (Moosmang et al., 2005). This might indicate (see Section 4.2) which may reduce L-VGCC activation by a given
that L-VGCCs are not always necessary to encode a spatial task, but input. Together these could be mechanisms by which strong or
might be critical for the subsequent strengthening of performance. old hippocampus-dependent memories might appear resistant to
This resembles other work in which incremental learning of a spa- destabilization under some conditions, but we expect that many
tial watermaze task has been observed to induce reconsolidation other mechanisms must also be involved. To reconcile this model
(i.e. Rodrguez-Ortiz et al., 2008). with the evidence indicating that calcium inux should suppress
Furthermore, several studies have observed that hippocampal cell ring via reduced sAHP (and other components of excitabil-
NMDARs are necessary for learning of an inhibitory avoidance ity), it is possible that sAHP is controlled by the sensitive CaV 1.3
task, but not following very weak pre-training or pre-exposure to (Gamelli et al., 2011; Lima and Marrion, 2007), but the much
the training context (Roesler et al., 1998, 2005). Thus is appears more prevalent CaV 1.2 (Clark et al., 2003; Hell et al., 1993) could
that NMDARs are not always necessary for memory strengthening, be primarily responsible for mediating plasticity (i.e. Clark et al.,
which may be mediated by reconsolidation (see Lee, 2008, 2009). 2003; Moosmang et al., 2005). Indeed, CaV 1.2 has specically been
As L-VGCCs can mediate calcium inux into neuronal spines and observed to form complexes with the activity-regulating AKAP,
dendrites (see Hoogland and Saggau, 2004; Kapur et al., 1998), this PKA, and 2 -adrenergic proteins (Davare et al., 2001; Oliveria et al.,
could position them as candidates for the initiation of memory 2007).
strengthening or updating. It has also been reported that block- We have discussed L-VGCCs here in detail because they may
ing L-VGCC activity does not impair learning, but it does disrupt also allow very different stimulation patterns to activate plasticity
remote memory retention (White et al., 2008; Woodside et al., relative to NMDARs (see Yuste et al., 2000 for discussion). In this
2004). One possible interpretation is that L-VGCCs could similarly way, they provide a putative mechanism at the level of an individual
assist in strengthening of memories during ofine reactivation or neuron by which different training procedures may dramatically
systems consolidation. Further indicating a role in the modication alter the types of reactivation necessary to induce memory lability.
of existing memories, it has been observed that L-VGCC activity is We propose that not only might the mechanisms of reconsolidation
necessary specically for memory extinction but not consolidation induction change due to training history, but they might also vary
(i.e. Cain et al., 2005), although this role has been contested (see depending on the characteristics of a given reactivation session.
McKinney et al., 2008; Schafe, 2008).
In another recent study using specic L-VGCC isoform knockout 4.1.3. Calcium-permeable AMPA receptors (CP-AMPARs)
mice, psychomotor sensitization was induced by repeated cocaine We will also briey propose a potential role for CP-AMPARs
exposure (Schierberl et al., 2011). Following long withdrawal from in memory reconsolidation. Transient insertion of CP-AMPARs has
cocaine, a cocaine challenge was observed to cause phosphoryla- been observed after strong synaptic stimulation (Plant et al., 2006),
tion of AMPAR GluR1 at Serine831 and rapid elevation of surface but there is evidence that they might remain at the synapse
GluR1 expression in nucleus accumbens (NAc) that was specically for hours or even days after behavioral experience (Bellone and
dependent on CaV 1.2 activation of CaMKII. As will be discussed in Lscher, 2006; Clem and Barth, 2006; Clem and Huganir, 2010;
Section 4.1.3., AMPARs exclusively containing GluR1 are permeable Conrad et al., 2008). In the forebrain of mature animals, these
to calcium and may be phosphorylated and rapidly inserted into receptors are typically comprised exclusively of GluR1 subunits
amygdala synaptic membrane following reactivation, possibly to (Geiger et al., 1995; Monyer et al., 1991). GluR1 phosphorylation by
mediate memory updating (Monls et al., 2009; Clem and Huganir, PKA, which may regulate CP-AMPAR trafcking, synaptic stability,

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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and activity (Blackstone et al., 1994; He et al., 2009), has also following unreinforced reactivation, it is impossible to be sure
been indirectly implicated in the induction of persistent extinction that these differences in gene activity following consolidation and
via reconsolidation-update (Monls et al., 2009). A GluR1 muta- reconsolidation were not caused by the absence of reinforcement
tion that prevents PKA phosphorylation at the Ser845 site causes during reconsolidation. Using multiple training and/or reactivation
reconsolidation-update extinction to recover over time or follow- procedures in each study may help identify the conditions under
ing a renewal procedure (Clem and Huganir, 2010). Wild-type which each mechanism is engaged during reconsolidation.
animals did not exhibit fear recovery following reconsolidation-
update extinction. Preliminary reports from Clem and colleagues 4.2. Intrinsic neuronal excitability, and the role of the cholinergic
have also indicated that CP-AMPARs may be reinserted during and adrenergic systems
memory reactivation one week after fear conditioning, which
allows persistent (reconsolidation-update) extinction to occur Just as calcium sources may regulate destabilization during
(Clem et al., personal communication). Maintaining CP-AMPAR reactivation, the overall excitability of a neuron may inuence
expression may preserve synaptic lability, and has been reported whether or not it will enter a plastic state in response to stimu-
to enable reversal of potentiation (Yang et al., 2010). In cortical lation. This topic has received considerable attention with regards
regions CP-AMPAR insertion may require NR2B activation (Descalzi to how specic neurons are initially recruited to encode a mem-
et al., 2012), while in other regions GluR1 insertion may require ory (Han et al., 2007; Wiltgen et al., 2004; Won and Silva, 2008).
L-VGCCs (Schierberl et al., 2011). Thus it is possible that in some However, excitability might also affect other metaplastic processes
brain regions NR2B, L-VGCC, and/or PKA activity during reactiva- at the neuronal level (see Abraham, 2008; Saar and Barkai, 2003,
tion could trigger trafcking of CP-AMPARs to the synapse, and that 2009 for discussion), including which neurons will be reactivated
the destabilization of memory prior to updating might rely on this during retrieval. Here we will present evidence that in some brain
CP-AMPAR activity. Another possibility is that the physical inser- regions excitability might be increased by learning to facilitate
tion of GluR1-containing AMPARs directly destabilizes the synaptic acquisition of the behavioral task (see Giese et al., 2001). After pre-
structure. Although inhibiting PKA following reactivation has been dictors are well established excitability might be reduced again,
observed to block memory reconsolidation and not destabilization which could limit further plasticity. We will also discuss how acti-
(Tronson et al., 2006), perhaps PKA activity is more important for vation of the cholinergic and adrenergic systems by the violation
destabilization of stronger memories when other plasticity mech- of existing environmental predictions might increase excitability,
anisms are suppressed. Corroborating this position, the study by and also determine the direction of plasticity.
Tronson and colleagues used just one pairing of tone and footshock,
while Monls et al. (2009) and Clem and Huganir (2010) used three 4.2.1. Neuronal excitability controls plasticity and is modulated
and six pairings, respectively. Although reconsolidation of a well by experience
trained conditioned cocaine memory is also reportedly blocked by Intrinsic neuronal excitability is the propensity of a neuron
a PKA-inhibitor infused into amygdala (Sanchez et al., 2010), this to re action potentials when stimulated (Zhang and Linden,
memory could have been weakened by extinction given between 2003). This is controlled by the expression, localization, and
training and reactivation. kinetics of voltage- and calcium-dependent channels, including
Interestingly, CP-AMPARs may also mediate a form of NMDAR- VGCCs, but also those that transmit potassium, sodium, and chlo-
independent contextual memory that depends on prior experience ride (see Foster, 2007). Unlike synaptic plasticity, changes to
with a similar task (Wiltgen et al., 2010), although this procedure intrinsic excitability will broadly alter activity at many or all post-
does not seem to induce protein synthesis-dependent reconsolida- synaptic regions. Perhaps the most commonly investigated forms
tion in hippocampus (Lee, 2008; Tayler et al., 2011). Finally, it has of excitability are slow and medium after hyperpolarization (sAHP
also been found that a reduction in L-VGCC calcium inux might and mAHP; together known as post-burst AHP), which determine
control CP-AMPAR up-regulation in inactive neurons (Thiagarajan the size and duration of hyperpolarization following trains of action
et al., 2005), and also that chronic genetic knockout of L-VGCCs potentials, and thus how frequently a neuron will re. sAHP is
might cause compensatory insertion of CP-AMPARs to mediate mediated primarily by apamine-insensitive, calcium-dependent
plasticity induction (Langwieser et al., 2010). Together the above potassium channels (Vergara et al., 1998) that are not yet fully
results could implicate the regulation of these receptors in an identied (see Sah and Faber, 2002; Power et al., 2011). The basic
experience-dependent manner (both in response to activity and mechanism, however, is that increased calcium accumulation dur-
lack thereof). We hypothesize that the temporary insertion of these ing stimulation will trigger more potassium to escape the cell
receptors shortly after memory reactivation may provide a portion membrane, leading to a longer inter-spike interval. In general it
of the calcium signal necessary to destabilize the trace. might be expected that a neuron that res less frequently should
be less likely to undergo synaptic potentiation, or that this poten-
4.1.4. Summary: different calcium sources for different tiation should be weakened (see Kirkwood et al., 1993). Thus, one
experiences? prediction is that an increased synaptic strength observed follow-
The differential behavioral and physiological conditions under ing acquisition of a behavioral task (e.g. Clem et al., 2008; McKernan
which these calcium channels may be recruited highlight the pri- and Shinnick-Gallagher, 1997; Power et al., 1997; Rioult-Pedotti
mary message of this review: that mechanisms observed to affect et al., 2000; Roman et al., 1993; Whitlock et al., 2006) might increase
reconsolidation under one set of training and reactivation condi- calcium inux during subsequent activity, and thus reduce ring
tions may not be recruited to reconsolidate similar types of memory rates. Thus, a memory might be predicted to be less likely to be
following other training or reactivation procedures. At present, it destabilized by reactivation due to reduced post-training excitabil-
is not clear from most reconsolidation studies if neurobiological ity.
mechanisms identied to be involved are limited to the specic Contradicting this prediction, most studies have actually found
training conditions used, or if they are fundamental components that learning seems to increase excitability within a brain region
of reconsolidation. For example, a very impressive study recently for hours or days (i.e. Aou et al., 1992; Brons and Woody, 1980;
reported qualitative and quantitative differences in the expression Disterhoft et al., 1988). For instance, it has been observed that train-
of a huge number of genes between consolidation and reconsolida- ing in hippocampus-dependent behavioral tasks in rabbits and rats
tion of contextual fear conditioning (Barnes et al., 2010). However, (such as trace eye-blink conditioning or Morris watermaze) can
because the mechanisms of reconsolidation were measured only cause a decrease in sAHP in hippocampal neurons (Moyer et al.,

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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1996; Oh et al., 2003). This sAHP reduction can be learning specic, watermaze) was facilitated (Zelcer et al., 2006). However, once
as slow-learning animals and those given sham training procedures the olfactory training was completed and a learning rule had been
have been found not to exhibit this reduced sAHP (Moyer et al., acquired (indicated by facilitate learning of novel odor pairs), sAHP
1996). There may be changes to intrinsic excitability even after a returned to baseline levels and watermaze learning was no longer
single learning trial, as cued and contextual fear conditioning have enhanced. This could indicate that in response to initial training
been shown to evoke increased sAHP in CA1, which can be reversed the hippocampus enters a learning state which readily enables
by extinction (McKay et al., 2009). The opposite pattern of changes the acquisition of new information. Once a learning criterion is
has been observed in the infralimbic cortex, which is known to reached, this facilitation could be suppressed via an increase in
be involved in extinction learning and expression (Santini et al., sAHP. This supercially resembles the reconsolidation data indicat-
2008). Many other studies have reported similar, lasting reduc- ing that reactivation might not destabilize strong or old memories
tions in sAHP in response to learning (i.e. Aou et al., 1992; Disterhoft (Inda et al., 2011; Suzuki et al., 2004; Winters et al., 2009).
et al., 1988), that do not occur following non-specic aspects of task One limitation of the above studies is that sAHP changes due
exposure (such as unpaired CS and US presentations or swimming to behavioral experience are not necessarily specic to memory-
in watermaze). encoding neurons, as it is difcult to infer if changes to excitability
occur only in the neurons that were recruited to encode expe-
4.2.2. Regulation of reconsolidation via neuronal excitability? rience, in non-encoding neurons, or both. However, Zelcer et al.
It has been proposed that training-induced increases in cortical (2006) reported that sAHP changes seem to happen in most neu-
and hippocampal excitability at encoding neurons might facili- rons within a brain structure of interest. Along with the observed
tate the replay or reactivation of these traces during the gradual learning enhancement across tasks, this suggests that experience-
(systems) consolidation of memories (Wiltgen et al., 2004). For dependent alterations of excitability may simply facilitate the
example, training rabbits in trace eye-blink conditioning reduces encoding of any information that relies on a given brain structure.
hippocampal sAHP for a duration that is consistent with a role in Essentially, the brain region could enter a learning state that pro-
consolidation from hippocampus into cortical regions (Thompson motes encoding of as much information as possible about events
et al., 1996). Furthermore, it appears that the reduction in AHP that are not yet well predicted, until rules or generalities can be
following olfactory discrimination learning precedes detectable derived from experience.
enhancement of synaptic connectivity in olfactory cortex by As this relates to reconsolidation, we expect that reduced sAHP
approximately two days, which is suggestive of a role of intrin- could simultaneously promote the post-reactivation destabiliza-
sic excitability in establishing the cortical connectivity associated tion of partially learned tasks and the encoding of new information
with rule-learning (Knafo et al., 2001; Saar et al., 1999). Specically, that could be relevant to the task being acquired, until the brain
it might be predicted that replay or reactivation of a trace may can identify and associate the reliable predictors of biologically
be promoted by increasing the likelihood that recently activated signicant events. In this way we expect that an increased sAHP
neurons will re, and thus that the connections between these after rule-acquisition may not entirely prevent lability of strong or
neurons might strengthen via coincident activation. If so, it seems old memories, but a decreased sAHP during learning might facili-
possible that reduced sAHP of memory encoding neurons could tate the destabilization of less well-trained memories. Accordingly,
also facilitate reconsolidation, as the capacity to reactivate and even after 8 training sessions of 60 pairings each, reconsolidation
strengthen memories during ofine processing periods (i.e. inactiv- can still be induced for a trace eye-blink task (Inda et al., 2005)
ity or sleep) of systems consolidation may be similar to what occurs that is similar to those described above. So a return of sAHP to
during online, experience-driven retrieval (see Robertson, 2012; basal levels after rule learning apparently does not prevent lability,
Sara, 2010; Stickgold and Walker, 2007). Although Diekelmann but we predict that it might limit what kinds of experience may
et al. (2011) have reported that reactivation during sleep and wake induce destabilization and also what information might be inte-
may have different effects on memory retention, this was demon- grated into a trace during a memory update. Extrapolating from
strated only using a post-reactivation interference paradigm. This the Saar et al. (1998) study mentioned above, new learning of novel
does not speak to the effects of reactivation during sleep and wake odor pairs might be integrated with existing odor discrimination
on their own, which could both serve to strengthen sparse cortical memories only when sAHP is reduced by promoting reactivation of
connections. We anticipate that increases to intrinsic excitability the original trace.
could generally promote the reactivation of a memory, whether the
function of this reactivation is to stabilize the trace during sleep or 4.2.3. A model for learning-dependent regulation of neuronal
to update the trace during behavioral experience. Indeed, animals excitability
that have just reached a learning rule for an odor discrimination How post-burst AHP is directly controlled is not yet well
task (see Slotnick et al., 2000) exhibit accelerated learning of novel established. As mentioned previously, post-training reductions of
odor pairs shortly after training a time when AHP is reduced in sAHP may be mediated by the suppression of yet to be identi-
piriform cortex but not ve days later when AHP has returned to ed, apamine-insensitive potassium channels (see Pedarzani and
baseline levels (Saar et al., 1998). One interpretation of this nding Stocker, 2008 for discussion). These sAHP-mediating calcium chan-
is that enhanced excitability might facilitate the integration of new nels may be primarily coupled to L-VGCCs (Bowden et al., 2001;
information with existing networks until they stabilize over many Goldberg and Wilson, 2005; Lima and Marrion, 2007; see Pedarzani
days. Such integration of old and new information could potentially and Stocker, 2008 for review), which suggests that calcium entry
be mediated by reconsolidation, by these channels (likely the CaV1.3 isoform in particular; Gamelli
Learning-induced sAHP reductions seem to last for days then et al., 2011) may increase sAHP. However, it must also be regulated
return to baseline. For instance, in the trace eye-blink task described by other pathways, as even complete blockade of L-VGCCs does not
previously (Moyer et al., 1996), CA1 pyramidal cells exhibited a eliminate the sAHP (Power et al., 2002). Some have reported that
reduced sAHP that lasted for 57 days, which is approximately potassium channels could be indirectly suppressed by activation
the time taken to learn this task to asymptote (Takehara et al., of mGluR1 (Ireland and Abraham, 2002) and/or kainate receptor
2003). During a multi-day training procedure of an olfactory GluR6 (Melyan et al., 2004; Fisahn et al., 2005), and maintained
discrimination task, sAHP has observed to decrease throughout by PKC (Seroussi et al., 2002). Others have convincingly implicated
the hippocampal neuron population sampled, at the same time noradrenergic and cholinergic activity in regulating post-burst AHP
that learning of another hippocampus-dependent task (Morris (see Disterhoft et al., 1999; Foehring et al., 1989). We will focus

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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on these latter two mechanisms because they have been convinc- 4.2.4. Adrenergic and cholinergic mechanisms of plasticity and
ingly implicated in adaptation to violations of predictions about the reconsolidation
environment (see Sara, 2009; Schultz and Dickinson, 2000). Because of their putative involvement in regulating excitability
Specically, increased cholinergic activity has been observed to and in modifying predictions about the world, it is worth noting
reduce post-burst AHP, and pre-training inhibition of this activ- that both acetylcholine and norepinephrine appear to play impor-
ity can prolong the time taken for olfactory rule-learning (Saar tant roles in reconsolidation (Baratti et al., 2009; Blake et al., 2011;
et al., 2001). However, in already trained animals, both AHP
Boccia et al., 2010; Debiec et al., 2011; Roullet and Sara, 1998).
and rule-facilitated learning of new odor pairs were unaffected However, most of this evidence suggests that disrupting the activ-
by cholinergic manipulations. This suggests that experience- ity of these neuromodulators can impair memory restabilization
dependent regulation of cholinergic receptors (see Van der Zee and with little indication of a role in destabilization. But in one recent
Luiten, 1999) might contribute to regulation of AHP via potassium study it was reported that a low dose of muscarinic cholinergic
channel modulation (also see Saar et al., 2007). As discussed by Oh receptor antagonist scopolamine (that had no effect on retention
et al. (2003), watermaze performance can be reduced by the appli- of inhibitory avoidance memory when it was administered imme-
cation of a muscarinic acetylcholine receptor antagonist (Brazhnik diately after reactivation) could prevent a memory impairment that
et al., 2003), which is also known to reduce the sharpening of was observed when reactivation was followed by exposure to an
hippocampal place elds (Riekkinen and Riekkinen, 1997) that nor- interference task (Blake et al., 2011). One interpretation of this
mally occurs toward the hidden platform location across learning nding is that precise acetylcholine signaling might mediate the
trials (Hollup et al., 2001). This lack of improvement across trials integration (or interference) of new information and reactivated
could reect difculties in identifying or integrating incrementally memories (see Robertson, 2012 for discussion of interference as
learned information. One model predicts that reduced choliner- memory integration).
gic activity may disrupt an animals ability to denote which of its It is also worth noting that many of the reported effects of
predictions about the world are unreliable (known as expected noradrenergic manipulations on reconsolidation have been derived
uncertainty; see Yu and Dayan, 2005). This would mean that from blockade of just one receptor type (-adrenergic receptors;
animals treated with a cholinergic antagonist might be impaired Debiec and Ledoux, 2004; Kindt et al., 2009; Milton et al., 2008b;
in their ability to use past experience to identify what is and Przybyslawski et al., 1999), and that these results been somewhat
is not predicted to occur in a given environment, which could inconsistent across the literature (i.e. Font and Cunningham, 2012;
be why they struggle to gradually learn complex tasks. Indeed Lee and Everitt, 2008; Milton et al., 2011; Muravieva and Alberini,
several researchers have suggested that cholinergic activity can 2010; Tollenaar et al., 2009). Thus, it should be considered how
also regulate switching between states of learning and retrieval the effects of long-lasting, receptor-specic manipulations of neu-
(Hasselmo, 2006; Hasselmo and McGaughy, 2004; Rogers and romodulator activity produced via application of pharmacological
Kesner, 2003). It further suggests that cholinergic control of AHP treatments could differ from the effects of endogenous changes
might play a role in the encoding of novelty until predictors are well in the phasic activity of these chemicals at all receptor subtypes.
established. Modulation of multiple receptors or systems may alter the form of
Along with acetylcholine, it has also been shown that nore- plasticity induced, or perhaps even prevent it entirely.
pinephrine can alter excitability in an experience-dependent For example, it has been observed that in visual cortex and hip-
manner (i.e. Saar and Barkai, 2009). It has been proposed that the pocampus, 1 - and -adrenergic agonists can facilitate LTD (while
adrenergic system is a critical part of the uncertainty model dis- preventing LTP) and facilitate LTP (while preventing LTD), respec-
cussed above (Yu and Dayan, 2005), with norepinephrine released tively (Seol et al., 2007; Huang et al., 2012). An M1 muscarinic
when a reliable cue no longer predicts an expected outcome receptor agonist had effects similar to the 1 -agonist. It was even
(unexpected uncertainty). Norepinephrine might block calcium- observed that these adrenergic agonists had comparable effects on
dependent enhancement of potassium channels and thus the synaptic plasticity during in vivo visual stimulation. Intriguingly,
increase of sAHP (Foehring et al., 1989; Pedarzani and Storm, 1993; when 1 and agonists were co-applied they did not have addi-
see Sara, 2009), which provides one mechanism by which both tive effects, but rather the inhibitory effects of each appeared to
L-VGCC activity and excitability could be increased in a reacti- cancel out, leading to a strengthening of either LTP or LTD depen-
vated neuron. However, as an odor discrimination task is acquired, dent on stimulation parameters. Amazingly, these agonists affected
norepinephrine has been observed to transition from increasing both potentiation and depression, but they had no effect on reversal
intrinsic excitability in piriform cortex to reducing it (Brosh et al., (depotentiation and de-depression) of already modied synapses.
2006; Saar and Barkai, 2009). If norepinephrine can signal when As noted by Huang and colleagues, the documented effects of
an established predictor does not occur with the anticipated out- -adrenergic antagonists on reconsolidation could be due to a per-
come (Yu and Dayan, 2005), then its increased release following missive inuence on induction of an LTD-like process. From these
violations of existing knowledge might reduce post-burst AHP to results, simultaneous blockade of 1 and receptors might also
help promote encoding of this unexpected information. Just as be expected to turn down the gain on potentiation and depres-
with acetylcholine, once predictors are reliably established, nore- sion, and possibly prevent destabilization of memories altogether.
pinephrine signaling may be reduced (or its residual release may Notably, these effects of the adrenergic manipulations reported by
begin to increase AHP) and may act to stabilize the acquired learn- Huang et al. were apparently independent of changes to intrin-
ing rule memory. In this way, norepinephrine and acetylcholine sic excitability and NMDAR activity, which suggests that these
signaling together may be critical for the brain to establish and neuromodulators might inuence metaplasticity mechanisms at
adapt predictive generalities about the world. multiple levels. The idea that interacting plasticity mechanisms
It is important to note that acetylcholine and norepinephrine may together permit or prevent memory destabilization will be
have very complex effects, which might be different for phasic discussed further in Section 4.6.
and tonic activation of many distinct receptor and cell types (see
Sara, 2009; Sarter et al., 2009 for related discussions). The afore- 4.2.5. Summary
mentioned model is thus simplied tremendously, however it does To summarize, it appears that for many behavioral tasks neu-
present one example of how the brain could promote new learn- ronal excitability initially increases after learning, which is followed
ing via excitability changes when environmental predictions do not by a return to baseline over time or as a learning rule is acquired.
match reality. As regulated by cholinergic and noradrenergic signaling (among

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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other systems), reduced AHP could help to encode information until bi-stable switch). However, training strength has not always been
the brain can extract reliable generalities about a given situation. observed to limit ZIP effectiveness (i.e. Kwapis et al., 2009). Clearly
Therefore, reducing post-burst AHP could be critical for promoting more work is needed to identify how PKM activity is regulated at
plasticity induction when a task is not yet reliably predicted, and so the synapse, and if under some conditions it could persist despite
it may inuence what reactivation procedures can trigger the desta- plasticity-initiation processes like calcium inux.
bilization of memory. In light of this proposed model, it is important
to consider in future research the role that intrinsic excitability 4.3.1.2. Blocking GluR2 endocytosis prevents memory modication?.
may play in reconsolidation. Whether the simultaneous blockade Just prior to initial submission of this review a highly relevant study
of multiple types of adrenergic and/or cholinergic receptors could was published which demonstrated behavioral and cellular effects
suppress memory destabilization should also be tested. In fact, we of applying membrane-permeable GluR23Y peptide during reacti-
surmise that some of the negative results of adrenergic manipula- vation of contextual fear memory on the reconsolidation-update
tions reported in the literature could be due to an impairment to extinction procedure (Rao-Ruiz et al., 2011). First it was reported
reconsolidation induction. that GluR23Y blocked the GluR2 endocytosis otherwise observed to
occur between 1 and 4 h after reactivation, and also the insertion of
4.3. Mechanisms of synaptic maintenance GluR2 that occurred 7 h post-reactivation. Although it was claimed
that preventing GluR2 endocytosis via this mechanism might not
Although regulation of calcium inux and neuronal excitabil- entirely prevent the induction of reconsolidation, as GluR23Y actu-
ity is likely critical for controlling whether or not a memory ally caused an increase in post-retrieval fear expression, it was
will enter a labile state, it is possible that mechanisms work- reported to prevent memory updating during the reconsolida-
ing to preserve synaptic structure could supersede them. That is, tion time-window. Using a reconsolidation-update protocol, in
plasticity-initiating signals, like calcium inux, may have little or which reactivation just prior to extinction has been observed to
no effect on memory if the synaptic composition remains stable. cause a permanent reduction in conditioned responding (Monls
Several mechanisms could feasibly work to maintain memory in et al., 2009), animals infused with the GluR23Y peptide into dorsal
this manner, and two examples will be discussed here. hippocampus CA1 region before reactivation exhibited signicant
post-extinction spontaneous recovery relative to rats given con-
4.3.1. PKM and the regulation of GluR2-containing AMPAR trol peptide. This potentially suggests that the extinction was not
endocytosis mediated by reconsolidation-update, but rather by consolidation of
The constitutively active, atypical isoform of protein kinase an inhibitory trace. Thus, GluR23Y might have prevented the puta-
C, protein kinase M-zeta (PKM), appears to be necessary for tively reconsolidation-dependent weakening of the conditioned
the maintenance of long-term memory and synaptic potentiation fear memory that has been proposed previously (Clem and Huganir,
(Sacktor et al., 1993; Sacktor, 2011). Inhibiting its activity via a 2010; Flavell et al., 2011; Monls et al., 2009; Schiller et al., 2010).
number of experimental manipulations, such as the infusion of the Rao-Ruiz and colleagues concluded that reconsolidation-update
-pseudosubstrate inhibitory peptide (ZIP), is observed to dramat- may not reect memory erasure (Clem and Huganir, 2010; Maren,
ically impair memory retention (Pastalkova et al., 2006; Serrano 2011), but rather a long-term reduction in fear expression via a re-
et al., 2008), while its genetic overexpression has been observed to evaluation and modication of the original fear trace (as discussed
enhance long-term memory (Shema et al., 2011). It is thought that by Soeter and Kindt, 2011a).
PKM is involved in maintaining GluR2-containing AMPAR inser- Rao-Ruiz et al. argue that maintenance of GluR2 by PKM
tion by opposing its regulated endocytosis (Migues et al., 2010). may not necessarily prevent the induction of reconsolidation, but
Migues et al. (2010) found that infusing a peptide, GluR23Y , that it may reduce interference or loss of memory perhaps by pre-
prevents this endocytic process (Ahmadian et al., 2004) also pre- venting memory updating during retrieval (while still permitting
vents the memory- and LTP-impairing effects of ZIP. PKM appears reactivation-induced strengthening). Taken one step further, if
to exist in a positive feedback loop through which it might induce its the removal of GluR2-containing AMPARs following reactivation
own local synthesis (Cai et al., 2011; Ogasawara and Kawato, 2010) reects the destabilization of memory, then this nding indicates
in order to preserve the structure of the post-synaptic density via that experience-induced memory strengthening may not necessar-
the maintenance of GluR2. ily require labilization at all just the insertion of new AMPARs. If
endogenous conditions exist under which AMPARs can be main-
4.3.1.1. PKM could prevent memory destabilization. It might be tained at the synapse (as when GluR23Y is administered) then
expected that this synaptic stability kinase might not just medi- perhaps under some conditions a synapse and the memory it
ate the maintenance of memory storage, but could also selectively encodes can be strengthened during reactivation without placing
control the entry of memory into a plastic state following retrieval it into a state where it can be weakened or disrupted pharmacolog-
(Dudai, 2009). As disrupting GluR2 insertion at the cell mem- ically.
brane is observed to cause plastic changes at the membrane and However, we feel that this ingenious study by Rao-Ruiz and
disruption of memory maintenance, preserving this association colleagues has not conclusively demonstrated that reconsolidation
between GluR2-containing AMPARs and post-synaptic scaffold- continues to be induced with GluR23Y onboard during reactiva-
ing proteins could potentially cause a synapse and the memory tion. First, the memory strengthening reported for animals given
it encodes to remain stable during reactivation under some condi- GluR23Y prior to two reactivation sessions could merely be due
tions. For instance, we have collected some preliminary evidence to the articial maintenance of GluR2 at the synapse, as perhaps
that strongly trained auditory fear memories (5 CSUS pairings) freezing would have been similarly elevated if animals had been
may be more insensitive to the amnesic effects of ZIP (Migues, given no reactivation between training and test 48 h later (this
Finnie, and Nader, unpublished observations). Thus, one possibil- was not directly evaluated). Second, it is not yet convincingly
ity is that learning could increase PKM expression or change its established that extinction following memory reactivation is medi-
structural localization such that it cannot be readily removed (even ated by reconsolidation. Recent work by Flavell et al. (2011) has
by the maximum dissolvable concentration of ZIP). The sustained demonstrated that blocking L-VGCCs (which is known to block
PKM activity may be sufcient to retain memory, or may re- the induction of reconsolidation for some tasks) also causes post-
engage its own production to recover any lost synaptic strength reactivation extinction to produce transient rather than persistent
(see Ogasawara and Kawato, 2010 for discussion of PKM as a behavioral inhibition. Although this nding suggests that Rao-Ruiz

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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may be studying a reconsolidation-mediated process, it is possi- to be critically involved in processes such as AMPAR exocytosis
ble that they have simply provided an elegant characterization of (Hayashi et al., 2000), proteasome translocation and activation
mechanisms mediating a phenomenon of persistent extinction. (Bingol et al., 2010), and gene transcription (von Hertzen and Giese,
Thus, an important question is if anisomycin or another amnes- 2005a). Its ability to lock into the autophosphorylated (partially
tic treatment would still impair memory following reactivation if autonomous) state, even after its activating calcium/calmodulin
GluR23Y was rst applied, or if the sustained AMPAR compliment signal has been removed, has made it an attractive candidate for
at the membrane would cause the memory not to destabilize. This plasticity and memory maintenance (Lisman et al., 2002). How-
experiment is ongoing in our lab. In either case, this intriguing ever, it has been repeatedly demonstrated that this kinase does
study provides evidence that at least some forms of memory mod- not impair late-LTP or long-term memory maintenance, but rather
ication may be prevented by the inhibition of regulated GluR2 LTP-induction and memory acquisition/consolidation (Buard et al.,
endocytosis. This position is further supported by a very recent 2010; Colbran and Brown, 2004; Irvine et al., 2005).
report that GluR23Y can block ocular dominance shift following But a recent study from the Lisman group has reported that
monocular deprivation in young mice (Yang et al., 2011b). Ocu- applying a high concentration of the peptides CN19 or 21, which are
lar dominance development was unimpaired by GluR23Y in mice known to block the catalytic activity of CaMKII at lower concentra-
without monocular deprivation. As visual development should be tions (Buard et al., 2010), can also disrupt its persistent binding
considered a form of memory encoding, these results could suggest with the NR2B subunit of NMDAR (Sanhueza et al., 2011). This
that updating this memory with novel information (visual input binding appears to require calcium/calmodulin or Thr286 phos-
from the non-dominant eye) requires GluR2 endocytosis. It has also phorylation, but once bound to NR2B even non-phosphorylated
been reported that GluR23Y can prevent both the depotentiation CaMKII can exhibit autonomous activity (Bayer et al., 2001). Con-
of amygdala synapses and the reduction in conditioned auditory sistent with the involvement of CaMKII in synaptic maintenance,
fear following extinction (Kim et al., 2007). Thus, GluR2 endocy- disrupting this macromolecular complex with a CN peptide was
tosis may be necessary to properly encode and/or integrate new observed to partially reverse saturated L-LTP and allow this synapse
inhibitory memories. to undergo additional LTP-induction. This inconsistency across
Finally, an unexpected twist in this literature is the observation studies may be explained by the inaccessibility of CaMKII bound
that acquisition of a conditioned drug approach behavior increased to NR2B to low concentrations of inhibitory peptide (Merrill et al.,
PKM expression in nucleus accumbens core, but infusion of ZIP 2005). Importantly, binding to NMDAR is known to lock CaMKII
into this structure led to a subsequent memory retention impair- into its autonomously active state (Bayer et al., 2001) by protect-
ment only in animals given reactivation after infusion (Crespo et al., ing the T286 site from dephosphorylation (Mullasseril et al., 2007).
2012). As ZIP is normally observed to affect memory in the absence Sanhueza et al. give a structural account for their nding, sug-
of reactivation (see Sacktor, 2011 for a recent review), one tenta- gesting that this complex may help anchor AMPARs to synaptic
tive interpretation is that in some cases reactivation may permit scaffolding proteins (as discussed in Bingol et al., 2010; Lisman and
PZM activity to be more readily disrupted, perhaps via structural Zhabotinsky, 2001). In this way, binding of CaMKII to NR2B may
synaptic changes and/or removal of a portion of PKM molecules maintain synaptic memory in a manner akin to PKM.
from the synapse. However, there are several reasons to doubt that this complex
could be involved in maintaining long-term memories in this man-
4.3.1.3. PKM and GluR2 maintenance summary. It is not clear if ner. For one, while CaMKII activity is increased by LTP induction
or how PKM or other GluR2 maintenance mechanisms might be or behavioral training, this appears short-lived in vitro (S.-J.R. Lee
retained to prevent plasticity induction, but it is a possibility that et al., 2009; Lengyel et al., 2004; though not Fukunaga et al., 1993)
deserves further attention. As discussed by Dudai (2009), this could and in vivo (Cammarota et al., 1998). Additionally, NMDARs can be
provide a mechanism for the controlled destabilization of select knocked-out for a week (though not a month) during the mainte-
synapses during both reconsolidation and regulated forgetting or nance of very remote memories without impairing their retention
memory decay. Therefore, it should be worth investigating what (Cui et al., 2004). This suggests that the NR2BCaMKII complex
endogenous systems mediate the weakening of PKMs stabilizing might not be critical (at least in very old memories) for reten-
grasp on synapses, and if some types of behavioral experience (such tion. That being said, residual NMDARCaMKII complexes (Leonard
as strong training) might cause it to persist at the synapse despite et al., 1999) and T286-phosphorylated CaMKII (Dosemeci and Jaffe,
stimulation that might otherwise initiate plasticity. 2010) have been consistently observed even under basal synaptic
states. Moreover, some computational models indicate that mul-
4.3.2. NR2BCaMKII protein complex tiple choreographed CaMKII holoenzyme complexes could remain
Another enticing candidate for the regulation of memory sta- active for years (Miller et al., 2005). Thus the very small propor-
bility is CaMKII. In this section we will discuss evidence that tion of activated CaMKII that binds to NR2B (Feng et al., 2011)
CaMKII may bind to NR2B-containing NMDARs to maintain LTP might be maintained at the synapse for long periods and go largely
and memory (see Lisman et al., 2012), and also how this persistent undetected, although it is not yet clear how this association would
interaction could prevent destabilization of information-storing impact memory maintenance. It might be predicted that the pres-
synapses by altering calcium signaling. Specically, we suggest that ence of this complex at the synapse could keep the activity and
this CaMKIINR2B interaction may protect information from loss localization of post-synaptic proteins locked in place.
both via a structural role in synaptic maintenance and by reducing
interference during subsequent learning or active decay (forget- 4.3.2.2. CaMKII binding to NR2B alters NMDAR activity and synaptic
ting) processes. plasticity?. As NMDARs can be briey knocked out without blocking
remote memory retention, we suspect that beyond a direct struc-
4.3.2.1. Involvement of CaMKII in LTP and memory maintenance?. tural role in maintaining synaptic composition, the CaMKIINR2B
It is thought that CaMKII is activated primarily by calcium entry interaction could modulate plasticity induction, perhaps by altering
through NMDARs, which can cause its autophosphorylation at the activity at NR2B-containing NMDARs. Sessoms-Sikes et al. (2005)
threonine 286 (T286) site (Lisman et al., 2002). If this autophospho- have reported that in HEK (kidney) cells, binding of Thr286 phos-
rylation is blocked, it prevents LTP induction (Malinow et al., 1989) phorylated CaMKII to NR2B-containing NMDARs causes increased
and can dramatically impair the formation of spatial memories desensitization of this receptor, which would typically reduce
(Giese et al., 1998). Autophosphorylated CaMKII has been reported its activity in a persistent negative-feedback loop. But others

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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have found that CaMKII phosphorylation can also increase overall Jenkins et al., 2010) NR2As, or CP-AMPARs, and suppress calcium
NMDAR activity, Kitamura et al., 1993). To reconcile these nd- inux through NR2B-containing NMDARs. We should again empha-
ings, Gustin et al. (2011) demonstrated that a mutation which size that L-VGCCs and NR2Bs have only been observed to play a
causes a loss of CaMKII Thr286 phosphorylation and reduced role in memory destabilization within the hippocampus (Suzuki
CaMKIINR2B binding seems to increase NMDAR activity in a man- et al., 2008) and amygdala (Ben Mamou et al., 2006), respectively.
ner that relies on an increased contribution of NR2Bs (but did Although it is possible that these mechanisms may interact within
not alter the expression of NMDAR subunits). Thus, it seems that a given structure, this has not been supported empirically. In the
CaMKII can specically reduce the activity of individual NR2B- case of CaMKII, we simply intend to imply that this common molec-
containing NMDARs. ular mechanism could serve to alter calcium channel activity in a
Although active CaMKII has signicantly higher afnity for the number of different ways across brain structures; including the pro-
C-tail of NR2B relative to NR2A (Barria and Malinow, 2005; Strack motion of L-VGCC activity in hippocampus and reduction of NR2B
and Colbran, 1998; Strack et al., 2000), a 12-subunit CaMKII holoen- activity in amygdala.
zyme may be capable of binding to multiple membrane proteins We tentatively propose that CaMKII binding to cell membrane
at once to maintain synaptic structure (Lisman and Zhabotinsky, proteins may change the input selectivity of a synapse and/or its
2001; Robison et al., 2005). Thus the CaMKII binding to NR2B plasticity response following memory acquisition. Indeed, CaMKII
might also allow for interactions of this complex with NR2A (Kim Thr268 autophosphorylation has been reported to decrease intrin-
et al., 2005). One effect might be reduced desensitization of NR2A- sic excitability specically following synaptic stimulation, which
containing NMDARs (as discussed by Sessoms-Sikes et al., 2005). A is mediated at least partially via an increase in sAHP (Sametsky
similar interaction may also occur for GluR1, as CaMKII bound to et al., 2009). This would be expected to impede further synap-
NMDARs may be held close to AMPARs (Tsui and Malenka, 2006), tic potentiation and possibly memory encoding. Furthermore, it
which might alter the persistence of GluR1 at the membrane (see has been observed that stronger synaptic stimulation is associated
Lisman et al., 2012 for discussion). Binding of CaMKII to NR2B might with increased NMDARCaMKII binding stability due to phospho-
also be important for Ser831 phosphorylation of GluR1 (see Halt rylation at this same Thr268 site (Bayer et al., 2006). Although it
et al., 2012), which can increase the activity of CP-AMPARs (Oh is clearly not possible to directly compare synaptic stimulation
and Derkach, 2005). In this way, the altered kinetics of many dif- to behavioral training protocols, this nding might suggest that
ferent calcium sources due to the NR2BCaMKII interaction could stronger training could be associated with increased stability of this
modify plasticity thresholds and/or pathways. Thus, if the binding protein complex, which, if blocked, could be reected by a dramatic
of CaMKII to NR2B is disrupted, thus blocking its interaction with acceleration in memory decay.
other membrane proteins, perhaps continued unmodied calcium
inux can cause partial depotentiation of the synapse. Although 4.3.2.3. Evidence for the involvement of NR2BCaMKII binding in
this might not account for the results observed by Sanhuesa and memory. One very recent study has reported that selectively block-
colleagues using hippocampal slices, we feel that it is a possibility ing the NR2B interaction with CaMKII (via knock-in mice with
that should not be ruled out. NR2B point-mutations) does not impair spatial watermaze learn-
Relatedly, phosphorylation of CaMKII at its Thr305/306 site is ing, but can block the consolidation and retention of this memory
known to have a dominant negative effect on constitutively active over time (Halt et al., 2012). These authors found impairment of
forms of CaMKII (Pi et al., 2010) and has also been implicated memory expression in knock-in mice only some time after 24 train-
in metaplastic processes in vitro (see Lucchesi et al., 2011). Pi ing trials spread across 6 days (on days 7 and 9 in two different
and colleagues have reported that Thr305/306 phosphorylation batches of animals). We should note that this is almost identical
of autonomously active CaMKII could cause plasticity induction to the training protocol previously observed to produce asymp-
to switch from LTD to LTP. As it has been observed that binding totic performance that would not undergo reconsolidation (Morris
of CaMKII to NR2B can prevent this Thr305/306 phosphorylation et al., 2006). While these authors convincingly proposed that this
(Bayer et al., 2001), this may indicate that the forms of plastic- blockade of NR2BCaMKII binding causes a decit in memory con-
ity which are inducible while NR2B and CaMKII are bound may solidation, we feel that the emergence of a decit only after a 1- or
be limited: LTP-like processes may be promoted, but LTD-like pro- 3-day post-training delay could be evidence of impaired memory
cesses may be reduced. Therefore, binding of NR2B to CaMKII could stability. In fact, we would predict that an unreinforced reactivation
prevent synaptic weakening, at least partly by reducing the inux or reversal trial after training might cause further impairment of
of calcium via NR2Bs. This could be reected in the aforemen- the training memory. Although these authors reported that several
tioned nding that daily application of an NMDAR-antagonist could physiological measures of NMDAR activity did not differ in these
maintain an otherwise short-lived spatial memory (Villarreal et al., mice, this was assessed under basal conditions. We would predict
2002), possibly by preventing an active decay process or memory that the channel properties of NR2B-containing NMDARs should be
interference mediated by NMDAR activation. Under endogenous altered by CaMKII primarily after potentiation has been established.
conditions, binding of CaMKII to NR2Bs following stronger train- We do not disagree with the interpretation that CaMKII bind-
ing might function in an analogous manner to offset homeostatic ing to NR2B is important for consolidation processes, but that one
processes which could otherwise return synapses to basal states function of this persistent association could be the alteration of cal-
(for related discussions see Rusakov et al., 2004; Vyazovskiy et al., cium transmission at a potentiated synapse to prevent decay or its
2008), or to inhibit further plasticity changes due to behavioral recruitment into competing memory networks. Indeed, in an ear-
experience (see Izquierdo et al., 1999; Morris, 1998 for relevant lier study it was found that acquisition and early (3-day) retention
ndings). of several different hippocampus-dependent tasks was normal in
In HEK cells, CaMKII has also been reported to tether to L-VGCCs heterozygous -CaMKII mice expressing reduced levels of CaMKII,
after it has been activated by calcium. This is known to facili- but that retention was impaired at 10-days and beyond (Frankland
tate entry of additional calcium through these channels (Abiria et al., 2001).
and Colbran, 2010; Hudmon et al., 2005). While this tethering At present, little work speaks to the involvement of CaMKII or
persists after the calcium signal fades, its enzymatic activity is the CaMKIINR2B complex in reconsolidation. For instance, CaMKII
still dependent on calcium/calmodulin. Together this work sug- activity was not required for retrieval of several types of mem-
gests that autophosphorylated CaMKII might work as a common ory (Szapiro et al., 2000), and no difference in its phosphorylation
mechanism to boost calcium inux via calcium channels (also see was reported following the testing of a strong inhibitory avoidance

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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memory, relative to untested controls (Szapiro et al., 2002) or in its reconsolidation can be induced in another region, at least in the
expression following retrieval of a contextual fear memory (Barnes case of auditory fear memories.
et al., 2010). This could indicate that hippocampus-dependent
reconsolidation might not require CaMKII activity. However, we 4.4.1. Network expansion
would expect that it is the presence of CaMKIINR2B associations at Prior discussions of memory stability have proposed that expan-
the time of reactivation (established during training) which might sion of the synaptic network that encodes a given memory may
affect reconsolidation induction. Overall changes to CaMKII activity decrease the likelihood it will undergo reconsolidation (Alberini
at or after retrieval likely says little about this protein interaction. et al., 2006) or be disrupted by post-reactivation amnesic treat-
ments (Frankland et al., 2006). The basis of this claim is the idea
4.3.2.4. Summary: predicted effects of NR2BCaMKII on reconsoli- that systems consolidation of hippocampus-dependent memories
dation. We will not propose that the NR2BCaMKII mechanism involves the gradual formation of new synapses and the increased
is involved specically in memory consolidation, maintenance, or involvement of cortical regions (Andersen and Soleng, 1998; Bailey
reconsolidation. Simply put, we expect that CaMKII binding may and Chen, 1988; Geinisman et al., 2001; Knafo et al., 2004; Nadel
preserve memory at least partly by protecting the information and Moscovitch, 1997).
encoded by a synapse from interference or active decay processes One aspect of this argument suggests that memories may
mediated at least partially by NR2B activation. become less sensitive to disruption with time or strength because
We would predict that blocking the NR2BCaMKII association the synapses engaged initially by learning are only a subpopula-
might increase the likelihood that a memory may enter a labile tion of those that exist after the growth of new synapses and the
state, above and beyond its direct effects on memory mainte- establishment of new connections. It was speculated that reconsol-
nance. It would be interesting to test if simultaneously blocking idation at remote points may only engage the subset of synapses
this protein interaction and NMDAR activity could partially rescue that were initially engaged by memory encoding (Alberini et al.,
the impairment of memory retention. Formation of this protein 2006). In this way, a young memory may have most of its synapses
association could be regulated by Ser1303 phosphorylation of destabilized during reconsolidation, whereas an old memory may
NR2B (Strack et al., 2000; Raveendran et al., 2009), but also the have a smaller proportion affected, leading to disruption at fewer
actions of specic CaMKII inhibitors (known as CaMKIIN- and - encoding synapses if this process is blocked. This could also be due
; see Lucchesi et al., 2011). Indeed, CaMKIIN activation occurs to a transition of initially hippocampus-dependent memory toward
rapidly after learning (Lepicard et al., 2006) and has been observed encoding cortical circuits. For instance, contextual fear condition-
selectively after contextual fear consolidation (Radwanska et al., ing may be sensitive to lesions of the hippocampus when acquired
2010; Barnes et al., 2010). Hence, if the post-training activity of during one session, but not when acquired across many learning
one or both inhibitors was reduced, it might produce a more sessions (Lehmann et al., 2009). Thus, perhaps cortical representa-
reconsolidation-resistant memory due to elevated CaMKII binding tions established during stronger training or over time might not
to NR2B. Once these proteins are bound in a persistent manner be reactivated and destabilized in the same manner as weaker or
(Bayer et al., 2006), it is not yet clear what mechanism induces their newer memories, which would reduce the effectiveness of manip-
dissociation (see Strack et al., 2000), although this could involve ulations aimed at impairing their retention.
the phosphorylation state of both CaMKII and the NR2B Ser1303 The other aspect of this argument might claim that the popula-
site (Meng and Zhang, 2002; Raveendran et al., 2009). However, tion of synapses reactivated during reconsolidation would expand
if the endogenous mechanism that dissociates this CaMKIINR2B along with the expansion that occurs during consolidation, but
complex were inactivated prior to memory reactivation, it might that this becomes increasingly difcult to disrupt with amnestic
prevent the induction of reconsolidation under some conditions. agents due to the expanded or distributed nature of the trace.
Much more work is required to evaluate whether the association Local infusions of amnestic drugs would clearly be most suscep-
of NR2B and CaMKII does in fact play a role in memory mainte- tible to this decreasing effectiveness (i.e. Frankland et al., 2006).
nance, and if it could regulate memory stability both during systems Critically, this position would suggest that it may not be that less
consolidation and following reactivation. of a memory is reactivated as it ages, but rather that as a trace
ages it is encoded by a larger memory network that becomes
4.4. Population-level mechanisms increasingly difcult to disrupt. This would lead to a lesser effect of
amnestic agents particularly those given via local infusions. It is
The aforementioned systems primarily involve changes that important to note that this might be more likely for hippocampus-
occur at the level of an individual synapse or neuron that could alter dependent tasks thought to undergo systems consolidation than
the reactivation cues necessary to induce destabilization. However, for non-hippocampal memories, although it is possible that other
mechanisms that work on the level of neuronal populations are memories may also undergo reorganization throughout the brain
also likely involved in regulating memory stability. For example, (for one example, see Winters et al., 2011).
the extinction of memory is thought to involve the formation of We feel that such changes to the memory-encoding network
a new inhibitory memory trace (Bouton, 2004), which may selec- over time could play a role in the increasing insensitivity to
tively involve other brain structures like intercalated nuclei (Li et al., memory-impairing manipulations, but it is debated whether this
2011; Likhtik et al., 2008; Maren, 2011; Polepalli et al., 2010), infral- can affect the proportion of the memory trace or the encoding
imbic, and prelimbic cortices (Mamiya et al., 2009; Sotres-Bayon
network that is destabilized by reactivation. For instance, Debiec
and Quirk, 2010). In the case of extinction, activation of inhibitory et al. (2002) reported that even 45-day old contextual fear mem-
circuits might somehow prevent memories from undergoing desta- ories which no longer rely on the hippocampus for expression
bilization and reconsolidation. Other population-level mechanisms seem to transiently re-engage the hippocampus when reactivated.
may similarly control whether memories enter a labile state fol- Critically, the remote memory was impaired by post-reactivation
lowing retrieval. As discussed above, Wang et al. (2009) found dorsal hippocampus infusions of anisomycin, suggesting that
that lesioning the hippocampus could prevent the down-regulation any cortical expansion is engaged by retrieval and disrupted by
of NR2Bs in BLA following strong training. This was observed to local hippocampal amnestic treatments. Relatedly, the aforemen-
allow the reconsolidation of a strong memory that was otherwise tioned work on schema integration indicates that exposure to
resistant to destabilization. The most parsimonious interpretation new information following retrieval of a strong, remote memory
is that one brain region may be capable of inuencing whether triggers cortical IEG activity not observed when encoding new

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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information without retrieval, or by retrieval alone (Tse et al., 2011). NMDARs (Kentros et al., 1998). Critically, when the animal is then
This indicates that while pharmacological manipulations during exposed to a context which consists of features from both environ-
reactivation could become less likely to disrupt a memory trace due ments (i.e. a box with attened corners), the ring patterns that are
to different regional effectiveness, reactivation itself likely triggers observed seem to be of one environment or the other (Wills et al.,
activity and plasticity in the expanded cortical regions recruited 2005; but also see Blumenfeld et al., 2006; Leutgeb et al., 2005 for
during consolidation. Furthermore, Frankland et al. (2006) reported other interpretations). A more box-like environment will trigger
that remote contextual fear memories were unimpaired by post- the square chamber representation, and a more rounded environ-
reactivation infusion of anisomycin into dorsal hippocampus, but ment will induce the ring patterns of the circular environment.
systemic injections caused a comparable impairment of recent This supports the principle of attractor dynamics, and suggests that
and remote memories. These authors proposed that as a memory pattern completion should allow partial cues to fully retrieve the
ages, the increased distribution of the trace throughout the brain memory of a past experience.
still permits its labilization following reactivation, but it becomes The problem faced by this system is what happens when novel
less vulnerable to disruption by locally applied post-reactivation stimuli are experienced in a familiar environment, as can be nec-
amnestic treatments. Contradicting this interpretation, a recent essary for induction of reconsolidation (i.e. Choi et al., 2010; Lee,
study by Winters et al. (2011) proposed that expansion of an object 2010; Rossato et al., 2007; Winters et al., 2009). It may allow for the
recognition memory trace from a form that was dependent on separation of events based on partial cues, but not for new details
perirhinal to a form that was also dependent on hippocampus to be encoded. Instead, the familiar features might be expected to
(caused by exposure to a new feature of the context) could still be merely drive retrieval of similar past experience: a system more
disrupted by post-reactivation anisomycin infusions into perirhinal consistent with trace dominance. To readily explain ndings of spa-
cortex. This could indicate that disrupting one region required for tial/contextual reconsolidation, this hippocampal encoding system
memory encoding might also block the memory encoded by other would be expected to permit subtle alterations of environmental
untargeted regions. ring maps without being attracted to existing states (see Knierim,
Evidently we are still far from understanding how the expansion 2002). Consistently, it is known that salient changes to an environ-
of a memory trace throughout neuronal circuits can inuence the ment can induce at least partial remapping of place elds (Fyhn
induction of reconsolidation. We propose that a memory should et al., 2002; Moita et al., 2003, 2004; Muller et al., 1999). For exam-
be capable of undergoing reconsolidation regardless of its corti- ple, moving the location of a well-learned hidden platform in an
cal expansion, though under some conditions this may reduce the annular watermaze task has been demonstrated to induce changes
effectiveness of brain region-specic amnestic manipulations. in the ring patterns of some place cells, though only transiently
(Fyhn et al., 2002). Similarly, moving two objects in an arena with
4.4.2. Hippocampus-mediated novelty-detection and dopamine stable elds induces remapping of the elds near the objects but
In addition to mechanisms that alter plasticity induction at a not the elds farther away (Lenck-Santini et al., 2005). Interestingly,
synaptic or neuronal level, there must also exist population-level however, discharge rates of these more distant elds were initially
mechanisms that control whether events are stored as new traces, reduced on the rst day, but then recovered on a second day of
as updates to old memories, or possibly not at all. Such a sys- exposure, which could reect some form of plastic modication
tem should allow sensory input to trigger the retrieval of encoded of the entire place map. In another study, exposure to immediate
memories, even if the content of these memories differs some- shock in a familiar context has been observed to cause remapping
what from current experience. This should allow past experience of the place elds of a minority of cells (Moita et al., 2004). Critically,
to guide behavior even in situations that are not identical. Theories partial environmental changes in these studies were not found to
of pattern completion, pattern separation, and attractor dynam- induce global remapping of place elds, as occurs during exposure
ics propose such cognitive features, which are commonly ascribed to a novel environment, but instead the local remapping of the place
to the hippocampal formation (Leutgeb and Leutgeb, 2007; Marr, elds for a subset of cells. How the brain accomplishes this par-
1970, 1971; Mizumori et al., 1989). This system may allow the par- tial remodeling of place memories is undoubtedly highly complex,
tial cues available during a given situation to trigger retrieval of a and we dare not attempt to propose a comprehensive model to
complete memory. It should then be capable of detecting whether explain this ability (see Fyhn et al., 2002; Poucet et al., 2000, 2011
a given event matches the previously encoded experience, and of for discussion).
identifying differences that exist between the two which require
memory storage (Lisman and Grace, 2005). 4.4.2.2. Hippocampal dopamine activity signals novel events?. One
part of this system that might be particularly important for remap-
4.4.2.1. Place-eld mapping to novel environments. Typically the ping is a hippocampal novelty-detection mechanism, which is
studies that have investigated these processes have measured place thought to depend on dopamine signaling from ventral tegmental
cell activity. These cells have long been known to re selectively area (VTA; Lisman and Grace, 2005; Lisman and Otmakhova, 2001;
based on the current location of a rodent within specic environ- Schultz et al., 1997). Very briey, it has been proposed that the CA1
ments (OKeefe and Dostrovsky, 1971; OKeefe and Nadel, 1978). region of hippocampus may serve to compare direct cortical inputs
The ring elds that quickly develop for each cell in each new envi- from the entorhinal cortex with indirect inputs from the trisynaptic
ronment have been noted for their spatial and contextual specicity pathway (entorhinal cortex to CA3CA1) where cortical informa-
(Muller and Kubie, 1987), as well as their remarkable persistence tion is used to retrieve relevant memories (Moser and Paulsen,
(Thompson and Best, 1990). In this way, it is believed that these 2001; Vinogradova, 2001). If the inputs match, no new informa-
stable ring patterns may be critical features of memory encoding tion is detected and plasticity may not occur (Lisman and Grace,
(OKeefe and Nadel, 1978). When animals are trained in one con- 2005; McClelland and Goddard, 1996). As mentioned above, this
text, such as a circular chamber, each cell begins to re selectively could be mediated by pattern completion via Hopeld networks
as the animal moves throughout the environment, and, once estab- (Hopeld, 1982), which are putative characteristics of hippocampal
lished, this ring pattern remains quite consistent during repeated architecture theorized to permit portions of a previously encoun-
exploration (Muller et al., 1987). Animals placed in a new envi- tered event to activate an attractor state that retrieves the rest of a
ronment, such as a square box, undergo global remapping of their specic memory (Treves and Rolls, 1992). If the inputs do not match,
place elds without disruption of existing maps (Bostock et al., this signals a difference between sensory input and existing mem-
1991; Wilson and McNaughton, 1993) in a manner that requires ory, and hence novelty. It has been postulated that via a descending

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and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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loop from hippocampus this mismatch signal might trigger activa- retention, however this reactivation session was administered only
tion of dopaminergic VTA neurons which release dopamine from 3060 min after training and was ineffective at 90 min (Sherry and
their afferents in CA1 (and elsewhere). This dopamine signal may Hale, 2005). From this methodology it is difcult to assess whether
act via D1/5 receptors to initiate or facilitate plasticity in hippocam- the antagonist affected the consolidation or reconsolidation pro-
pus (Ciliax et al., 2000), and thus encode the novel information cess, and also if it would prevent memory destabilization (as the
(Lemon and Manahan-Vaughan, 2006). Elsewhere in the brain this memory was likely already in a labile state). In another study it
phasic dopamine release to novelty may preferentially activate D2 was observed that systemic application of amphetamine, which
receptors in order to suppress and alter established behavioral is known to increase the activity of dopamine and other biogenic
responding (Bilder et al., 2004). amines at the synapse (Sulzer et al., 2005), can enhance reconsoli-
dation of a conditioned place preference memory (Blaiss and Janak,
4.4.2.3. Novelty-signaling by dopamine and reconsolidation. As 2006). However, this treatment did not target specic mechanisms
applied to reconsolidation, this model would suggest that attractor or brain regions. Nevertheless, it is possible that this enhanced pref-
states may allow reactivation cues to retrieve a complete mem- erence was due to a strengthening of the memory trace due to a
ory trace, and the presence of novel stimuli (or absence of familiar facilitation of plasticity induction, although there are many other
stimuli) may trigger dopamine release which could induce lability interpretations.
of the complete trace in order to update the memory. Unfortu- In another study investigating consolidation and reconsoli-
nately, to our knowledge few studies have directly investigated dation, D1/5 activity was modulated in ventromedial prefrontal
the relationship between reconsolidation and place eld activity, (vmPFC) to observe the effects on object recognition memory
and none has directly examined the involvement of hippocampal (Maroun and Akirav, 2009). However, interpretation of these
dopamine activity in reconsolidation. What would have happened results is not straightforward. Animals were either given habitua-
in the aforementioned studies (wherein a small population of place tion or no habituation to the training environment before exposure
elds were re-mapped by changes to a familiar environment) if to the novel objects. Thus, for animals given habituation the object
a reconsolidation blocker were applied during exposure to the exposure may actually have served to update the existing context
altered environment? Would only the subpopulation of cells that memory with new features via reconsolidation. This group was
remapped be disrupted? Or would partial remapping render labile impaired by D1/5 antagonist and unimpaired by D1/5 agonist. It
the otherwise stable pattern of place-cell ring to the entire envi- could be argued that for these animals D1/5 activity in vmPFC was
ronment? required to update the context memory to incorporate the new
We are not aware of any study that has applied amnestic treat- objects. Indeed, in rodents and primates it is thought that medial
ments during procedures that induce partial remapping while PFC processes or integrates spatial and identify information about
monitoring place elds. For instance, one study found that global objects (Barker and Warburton, 2008; Wilson et al., 1993). Fur-
remapping to a novel environment was not initially prevented by thermore, animals already exposed to the objects were impaired
injection of an NMDAR-antagonist, though it did impair stabiliza- by D1/5 agonist infusion prior to re-exposure, but D1/5 antagonist
tion of these elds without affecting the place map of a previously infusion only impaired reconsolidation in animals not habituated
explored environment (Kentros et al., 1998). Another group found to the context. There is no obvious explanation for this differential
that anisomycin infused during re-exposure to a familiar envi- effect. Lastly, these treatments were conned to vmPFC where the
ronment failed to destabilize its place elds, though this context effects of D1/5 activity might be rather different than in hippocam-
was highly familiar (10 prior exposures) and evoked highly stable pus. As some have reported that tonic prefrontal D1 activation may
ring patterns (Agnihotri et al., 2004). Few would expect such well- maintain cognitive stability, it is possible that the hours-long sup-
trained memory to be rendered labile by additional exposure (for pression of these receptors by antagonist might actually promote
comparable results see Biedenkapp and Rudy, 2004; Lee, 2010). The behavioral plasticity (Bilder et al., 2004). Maroun and Akirav pre-
most convincing evidence may be deduced by combining the afore- sented an elegant interpretation of their consolidation data with
mentioned ndings of Lee (2010) and Moita et al. (2004). Together regards to optimal levels of arousal, but it is difcult to disam-
these studies demonstrate that animals receiving immediate shock biguate their reconsolidation ndings.
in a previously explored environment exhibit partial place eld Finally, a very recent study using fear conditioning in humans
remapping in this environment, which is a procedure observed revealed correlational evidence that dopamine might mediate
by Lee to be mediated by reconsolidation. Thus, pharmacological reconsolidation induction (Agren et al., 2012). Humans with
disruption of reconsolidation might be predicted to interfere with the common Val allelic variant (Val/Val homozygotes) of the
this remapping. But would it also have blocked the stable place catechol-O-methyltransferase (COMT) gene showed enhanced
elds that were not remapped following delivery of the footshock? re-acquisition of a CS-evoked skin-conductance response after
A study that empirically tests this question is clearly warranted. extinction relative to individuals with the Met allele. Val/Val
At the very least, preliminary evidence seems to indicate that this individuals also showed a signicant impairment of reacquisi-
system is indeed capable of identifying novel stimuli and encoding tion when extinction was given shortly after memory reactivation
this information via alterations to place representations. This could (reconsolidation-update). The Val allele is known to increase
make place cell studies an ideal approach to studying reconsolida- dopamine catabolism which should reduce synaptic dopamine lev-
tion. els following release (see Weinshilboum et al., 1999). However,
Very few studies have explicitly investigated dopamines role in because of these chronically low dopamine levels, D1 expression
reconsolidation, and even fewer have targeted their function in hip- and availability may also be dramatically upregulated in Val/Val
pocampus. We would predict that memory destabilization should individuals (Slifstein et al., 2008). Interpreting the net effect of this
only occur only when novel information is experienced by acti- genetic variant on D1 activation is not straightforward, but it sup-
vating hippocampal D1/5 receptors. In one relevant study, place ports the position that D1 receptors might play an important role
cells of D1 knock-out mice exhibited a reduced responsiveness to in updating memories with new information (either strengthen-
the features of a new environment, suggesting that these animals ing or weakening a fear memory after consolidation). Importantly,
may fail to identify or encode novelty (Tran et al., 2008). In a set it has been hypothesized that the Val allele may confer reduced
of behavioral experiments using day-old chicks it was reported tonic and enhanced phasic dopamine levels, which could function
that a systemically injected D1/5 receptor antagonist applied 5 min to reduce the stability of neural networks (Bilder et al., 2004). Phasic
before retrieval of a passive avoidance task impaired memory dopamine release should mediate novelty signaling (Schultz, 2002).

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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However, COMT degradation of dopamine may be more common L-VGCCs, though little exists at present. In one study it was reported
in regions with low expression of dopamine transporter, like pre- that a variety of D1 agonists have an enhancing effect on L-VGCCs,
frontal cortex (Matsumoto et al., 2003), and may be much rarer in though only in partially depolarized CA1 neurons (Hernndez-
hippocampus (see Myhnen et al., 2010). Lpez et al., 1997). In some striatal neurons, PKA activated by D1 has
In one study using the aforementioned event arena, animals been shown to enhance CaV 1.2 L-VGCCs activity (Surmeier et al.,
with a well-trained set of paired odorlocation associates had their 1995). Furthermore, in the subthalamic nucleus, D5 activity may
storage of new pairs disrupted by NMDAR- or D1/5-antagonist enhance L-VGCC activity via PKA activation (Baufreton et al., 2003).
infusion into hippocampus, though neither drug disrupted main- The direct role of dopamine in plasticity is contested. Application
tenance of the previously encoded pairs (Bethus et al., 2010). of a D1 agonist to hippocampus neurons has been found to increase
However, short-term acquisition of new pairs was unimpaired by LTP threshold and promote LTD (Yang et al., 2011a), but might
either treatment. Tentatively this could indicate that dopamine also inhibit depotentiation (Otmakhova and Lisman, 1998). Others
activity is necessary for this new information to transition into have reported that whether LTP or LTD is facilitated may depend
long-term storage via integration with existing schemas. This may on the baseline dopamine activity of the preparation, with in vivo
be involved in routing memory encoding via hippocampus into cor- dopamine levels promoting LTP (Otani et al., 2003). Lemon and
tical structures, but it does not seem to gate the initial encoding Manahan-Vaughan (2006) found that D1/5 activity could promote
of information. However, whether dopaminergic activity regulates both LTP and LTD in hippocampus in vivo. But a very impressive
the destabilization of memories during their retrieval remains to be recent study has indicated that activation of GS protein-coupled
determined. The present lack of relevant ndings prevent us from receptors (which include D1/5) can simultaneously promote poten-
assembling a clear interpretation about the role of dopamine in tiation and inhibit depression both in vitro (in visual cortex and
initiating reconsolidation in hippocampus in response to novelty. hippocampus) and in response to experience in vivo (in visual cor-
tex; Huang et al., 2012). This did not simply slide the LTP/LTD
4.4.2.4. The effects of dopamine on synaptic plasticity and metaplas- threshold (Huang et al., 2012). Rather, this work indicates that
ticity. The ways in which dopamine may promote plasticity are far LTP may be rapidly enhanced and LTD prevented, downstream of
too complex to discuss here in detail, but often it is observed that NMDAR activation and independent of its subunit composition, by
D1/5 activation tends to facilitate plasticity (LTP and/or LTD) in hip- GS agonists. Together this work could indicate that dopamine can
pocampus (Lemon and Manahan-Vaughan, 2006; Otani et al., 2003; both inuence metaplasticity of calcium channels, and control the
but see Jay, 2003 for a review). One particularly relevant mechanism form of plasticity that can be induced by a given calcium signal.
may be the interaction between dopamine receptors and NMDARs
(see Cepeda and Levine, 2006), although some of this work has
been performed in non-hippocampal tissue. For instance, D1 activ- 4.4.2.5. Summary: hippocampus dopamine and destabilization dur-
ity has been observed to uncouple D1NR1, while promoting LTP ing novelty?. Based on the presented evidence, we feel that this
and NR1CaMKII coupling (Nai et al., 2010). It has also been found dopamine-based system may be ideally poised to regulate mem-
that binding of D1 and NR2A can inhibit NMDAR activity in hip- ory destabilization based on both conditions that seem necessary
pocampal neurons (Lee et al., 2002). In prefrontal cortex neurons it for memory updating via reconsolidation. First, attractor dynam-
has been observed that D1 activity can increase NR2B expression via ics should ensure that sufcient similarity to a prior memory will
tyrosine phosphorylation (Gao and Wolf, 2008) and in hippocam- evoke its retrieval (an attractor node), and second, the novelty-
pus it can reduce the NR2A:NR2B ratio, which could affect plasticity detection system could gate the processing of information in a
induction (Varela et al., 2009). In this study D1/5 activity was also manner that only activates encoding mechanisms when unfamil-
found in facilitate transmission mediated by NR2Bs and suppress iar features are detected (see Blumenfeld et al., 2006). However,
transmission mediated by NR2As. Together this work suggests that we should note that pharmacological approaches used to investi-
D1/5 activity may often enhance NR2B expression and activity. Per- gate these predictions may be complicated by the fact that phasic
haps most impressively, Varela and colleagues also demonstrated rather than tonic dopamine activity may play a primary role in
that endogenous D1/5 activity may increase the responsiveness of novelty signaling (see Schultz, 2002). Thus, application of selec-
CA1 region NMDARs to inputs coming from the trisynaptic pathway tive dopamine agonists or antagonists may be difcult to interpret.
through CA3, rather than inputs from the monosynaptic corti- We anticipate that techniques with more temporal control over
cal/entorhinal pathway (due to the higher NR2B:NR2A ratio at dopamine activity, like optogenetics, may be necessary to reveal its
CA3CA1 versus entorhinalCA1 synapses). The model proposed role in reconsolidation. We should also note that D5 are likely the
by Lisman and Otmakhova (2001) would predict that a bias toward most common dopamine receptor in hippocampus (see Lisman and
CA3 input to CA1 may help strengthen recently encoded mem- Grace, 2005), and thus could support encoding of novel information
ories. Based on work showing that CA3 place elds may remap in this structure (Lemon and Manahan-Vaughan, 2006), However,
on a rst trial in a new environment, followed by remapping in in brain regions like pre-frontal cortex, D2 receptors may play the
CA1 on subsequent trials given shortly after (I. Lee et al., 2004), primary role in cognitive exibility through their response to phasic
this could support a position wherein dopamine signaling by nov- dopamine release during novelty, while D1 activity may promote
elty induces changes in CA1 input selectivity, which allows it to cognitive stability by responding to tonic release (see Bilder et al.,
process and integrate this new information into existing memory 2004 for discussion). It is also worth noting that we have discussed
networks (see Leutgeb and Leutgeb, 2007 for a related model). Thus, novelty-detection with reference only to dopamine, but it may also
dopamine activity in the hippocampus may directly inuence plas- critically involve other neuromodulators like acetylcholine (see
ticity processes, but may also be capable of altering metaplasticity Hasselmo et al., 1995; Meeter et al., 2004).
mechanisms like NR2A:NR2B ratio. We should remind the reader
that there is less evidence for experience-dependent regulation of
NMDAR subunits in hippocampus than for other brain regions, but 4.5. Other stability mechanisms
studies still indicate that NR2B:NR2A ratio in hippocampal neu-
rons can change dramatically in response to synaptic activity (i.e. It is not possible to comprehensively review all mechanisms that
Bellone and Nicoll, 2007; Jung et al., 2008; Lee et al., 2010). could regulate the reactivation procedures that can destabilize a
Perhaps more relevant to memory reconsolidation in the hip- memory, but many other candidates exist. Several more will be
pocampus would be evidence for the interaction of D1/5 and briey summarized in the following.

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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4.5.1. Group I metabotropic glutamate receptors (mGluRs) 4.5.2. Epigenetic regulation


Group I mGluRs (mGluR1/5) have been convincingly demon- Epigenetic changes could stably alter the expression of specic
strated to affect metaplasticity (Abraham, 2008; Clem et al., 2008) genes necessary for plasticity. They are known to inuence the stor-
and experience-dependent priming in vitro and in vivo (Bortolotto age and maintenance of long-term memory (Swank and Sweatt,
et al., 1994; Cohen and Abraham, 1996; Cohen et al., 1998; Popkirov 2001; Levenson and Sweatt, 2005), but also the capacity of pre-
and Manahan-Vaughan, 2011; Rudy and Matus-Amat, 2009). For viously activated synapses to undergo additional changes (Lubin
example, as mentioned previously an mGluR1/5 antagonist can and Sweatt, 2007; Maddox and Schafe, 2011). Lubin and Sweatt
impair NMDAR-independent strengthening of synapses already reported that contextual fear memory reactivation caused an up-
potentiated by single whisker stimulation (Clem et al., 2008). It regulation of NF-B signaling via IkK which elevated histone H3
was also found to prevent the enhancement of conditioned habit- phosphorylation. Blocking this cascade was found to impair recon-
uation learning that is observed following whisker stimulation. solidation, but pharmacologically elevating histone acetylation was
This indicates that group I mGluRs might mediate strengthening found to rescue this impairment. Epigenetic regulation might also
of connections and encoding of memories specically at synapses control the conditions under which a memory might undergo
that have previously undergone plasticity following experience. extinction (see Stafford and Lattal, 2011 for a recent review). Via
Clem and Huganir (2010) have also reported that mGluR1 activ- epigenetic mechanisms, it could be imagined that expression of
ity during post-reactivation extinction (reconsolidation-update) plasticity-related genes could be suppressed following some types
is necessary to persistently suppress a conditioned auditory fear of memory encoding to prevent changes to the stored information.
response. In this study mGluR1 activity might allow reconsolida-
tion to be initiated such that new inhibitory information can be 4.5.3. Neurogenesis
incorporated into this memory, thereby permanently weakening Neurogenesis in the hippocampus (and possibly olfactory cor-
fear expression. tex) could also help maintain memories (Abrous et al., 2005). For
We would expect that release of intracellular calcium could also instance, some evidence indicates that newborn neurons might
play a role in this mGluR cascade (Mellentin et al., 2007; Sajikumar help separate new memories from old ones and prevent interfer-
et al., 2009). Activation of these signals may together be involved ence between similar traces (Clelland et al., 2009; Wiskott et al.,
in the production of plasticity proteins (like PKM and/or BDNF) 2006). It has been proposed that based on which generation of
for capture during subsequent heterosynaptic activity, which can new neurons is recruited to store a memory, the brain can even
cause weak stimulation to evoke long-lasting changes in vitro extrapolate a temporal sequence of events (see Aimone et al., 2006).
(Sajikumar and Korte, 2011). Importantly, Sajikumar and Korte However, although learning may enhance the birth, development,
found that the same group I mGluR agonist used by Clem and and survival of new neurons (Ambrogini et al., 2010; Gould et al.,
colleagues primed a local dendritic region to undergo subsequent 1999; Leuner et al., 2006), it is not clear how this system might
plasticity. It is possible that memory reactivation could likewise be selectively implemented by the brain to control the induction
prime synapses via mGluR1/5 activation, and learning that occurs of plasticity of a given memory. One impressive recent study has
shortly after (as during reconsolidation-update extinction) may found that young adult-born dentate gyrus neurons may be broadly
recruit these new proteins to strengthen or weaken the synapses. In tuned to weak synaptic activation, but this input specicity and
fact, it is known the a group I mGluR agonist can induce depoten- threshold increases as they mature such that this brain region
tiation of amygdala synapses previously potentiated by auditory can both encode and orthogonalize memories (Marn-Burgin et al.,
fear memory consolidation (Kim et al., 2007). However, mGluR- 2012). A reduction in the birth of neurons, as occurs with age, could
dependent depotentiation was not observed if memories had been potentially be a cause of increased interference or source confusion
labilized by reactivation (Kim et al., 2010). This mGluR1/5 agonist between memories (Koutstaal and Schacter, 2001), which could
also impaired memory retention when infused 1 h, but not imme- be due to overwriting of similar events when memories are not
diately after reactivation. One interpretation is that mGluR1/5 properly orthogonalized. Furthermore, one study has suggested
activity might induce synaptic destabilization and weaken memory that the growth of new neurons in hippocampus can play a role in
if it is not already labilized. Although Kim and colleagues observed the apparent clearance of hippocampus-dependent memory traces
no agonist-evoked changes at unpotentiated synapses, others have over time (Feng et al., 2001). Therefore we suspect that this system
reported that application of a group I mGluR agonist can cause may play a general role in protecting memories from being over-
transient synaptic depression (Cohen et al., 1998; Raymond et al., written, although it is not clear if different types of training could be
2000), which can lower the threshold for plasticity during sub- more or less likely to recruit young neurons (see Barker et al., 2011
sequent activity. As transient reduction of synaptic strength has for discussion of neurogenesis and reconsolidation in seasonal song
been observed following memory reactivation (Clarke et al., 2010; learning birds).
Rao-Ruiz et al., 2011), we argue that in some situations this could
potentially be mediated by mGluR1/5 activation and might reect 4.5.4. Extracellular matrix (ECM)
AMPAR endocytosis during destabilization. Synaptic and mnemonic stability could also be controlled by
Although it has been reported that mGluR1/5 antagonists actu- ECM proteins, which have been implicated in the regulation of
ally disrupt reconsolidation (not destabilization), these studies memory extinction (Gogolla et al., 2009), reconsolidation (Brown
have been performed only in newborn chicks and with ambigu- et al., 2007), and the localization/activity of membrane proteins
ous results (Gieros et al., 2012; Salinska, 2006). For example, like AMPARs and NMDARs (Dityatev et al., 2010). Briey, it has
in the case of the mGluR5 antagonist, the effect on avoidance been suggested that these extracellular proteins can bind with
memory reconsolidation was attributed to a retrieval impairment. membrane proteins and help to maintain synaptic structure, con-
Post-reactivation application of a mGluR1 antagonist caused a nections, and activity (Dityatev et al., 2010). With respect to
short-lasting (<4 h) impairment of avoidance memory that was memory, the Gogolla et al. (2009) found that degrading amygdala
not observed in non-reactivated subjects. It is not apparent why perineuronal nets could cause fear extinction to erase (persis-
this disruption was only temporary, but it could indicate that the tently suppress) a conditioned fear response. This indicates that
memory trace was not properly labilized. Together the evidence ECMs may stabilize existing synaptic structures, but their absence
reviewed here leads us to predict that group I mGluR activity is can cause a loss of encoded information when a memory is chal-
likely to play an important role in destabilization of some memories lenged by retrieval or related experience. The involvement of
following their reactivation. ECMs is not limited to the amygdala, and their stabilizing effects

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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may be so powerful that even adult ocular dominance columns production of many plasticity-related proteins, including AMPARs
can be rapidly remodeled if perineuronal nets are dissolved in for insertion during the establishment of the memory trace or
visual cortex (Pizzorusso et al., 2002). Blocking one type of ECM PKM to stabilize these receptors at the synapse. To drive protein
(reelin) with antisense oligonucleotides can also prevent the mat- synthesis, activation of transcription factors like cAMP-responsible
urational decrease in NR2B-mediated currents (Sinagra et al., element binding protein (CREB) and NF-B might mediate the gene
2005). Relatedly, blocking the interaction of ECM with receptors transcription and translation necessary for all forms of reconsol-
(called integrins) that are attached to the neuronal cytoskeleton idation (de la Fuente et al., 2011; Kida et al., 2002; Merlo et al.,
can prevent LTP stabilization and promote depotentiation (Chun 2005). During all forms of reconsolidation, the proteasome pathway
et al., 2001; Kramr et al., 2002). In hippocampus, removal of might also be recruited to destabilize synaptic connections before
one major constituent of extracellular matrices, hyaluronic acid they can be altered during reactivation (Kaang and Choi, 2011).
(HA), can reduce currents and calcium inux mediated by den- However, even the degradation system could rely at least partially
dritic L-VGCCs, as well as a L-VGCC-dependent component of LTP on other proteolytic mechanisms, such as the lysosomal pathway
(Kochlamazashvili et al., 2010). This was also found to impair con- (see Ciechanover, 2005). For instance, it has been observed that
textual fear consolidation. Together these results lead us to propose GluR1-containing AMPARs internalized by AMPAR activity may be
that the ECM could help prevent memories from being destabilized trafcked to the lysosome for degradation in a ubiquitin-dependent
when related information is experienced, and disrupting the ECM manner, while those internalized due to NMDAR activity may be
might prevent the robust encoding of new memories. internalized in a ubiquitin-independent manner that allows them
Despite this prediction, several reports indicate that disrupt- to be recycled back to the membrane if they are phosphorylated
ing the activity of matrix metalloproteinases (MMPs), which by PKA (Schwarz et al., 2010). Although Lac (used to selectively
are thought to play an important role in ECM remodeling (see block the proteasome in several reconsolidation studies) may also
Matrisian, 1992), can block reconsolidation of conditioned place impair lysosomal processing (Ostrowska et al., 2000), in either case
preference and auditory fear memories (Brown et al., 2007, 2009). it remains possible that the specic degradation systems recruited
This in unexpected as we would predict that blocking ECM remod- during reconsolidation could depend on reactivation conditions.
eling might prevent memory destabilization. However, some of the Again, as with the sources of calcium activated during stimula-
results were unusual relative to those typically reported in recon- tion, this is unlikely to be an all-or-nothing substitution, but instead
solidation studies. For example, fear memory was only impaired the role played by each proteolytic pathway could change depend-
by MMP inhibitors at 7 days, but not 24 h after reactivation (Brown ing on experimental conditions. Other mechanisms common to all
et al., 2009). Furthermore, in their 2007 study the effect of MMP forms of reconsolidation have been discussed in detail elsewhere
inhibitor was only assessed following post-extinction reinstate- (Alberini, 2005; von Hertzen and Giese, 2005b; Tronson and Taylor,
ment of conditioned place preference. It could be argued that 2007). It remains to be tested whether such mechanisms are indeed
blocking MMPs only prevented the training-induced recovery of sites of convergence initiated by all forms of reconsolidation, or if
behavior that had been weakened by extinction. Perhaps recon- they may be specic to only some instances of reconsolidation.
solidation of the place preference memory was unimpaired by The convergence of plasticity mechanisms on particular path-
MMP inhibition, and instead long-term suppression of the extinc- ways would predict that a number of systems could each
tion memory was prevented. Indeed, in a prior study these authors initiate similar plasticity cascades. Some potential initiators were
observed increased activity of one MMP (MMP-9) in medial pre- described throughout Section 4. In this sense, we doubt that there
frontal cortex only when cocaine reinstatement of place preference is any one receptor or channel that solely mediates destabilization.
followed many extinction trials, but not when extinction was While activation of a particular mechanism may be necessary (per-
not given (Brown et al., 2008b). In general these seminal studies haps even sufcient) to induce reconsolidation in a specic brain
by Brown and colleagues provide convincing evidence that ECM region, it is likely that interaction among many systems (each with
remodeling plays a critical function in reconsolidation, but precise variable involvement) engages plasticity. We have perhaps identi-
characterization of this role is warranted. ed those that play strong roles within particular regions (i.e. NR2B
within BLA; L-VGCCs within hippocampus), but for others it may
4.5.5. Summary be more difcult to dissociate involvement in destabilization from
Evidently there are numerous intra-, inter-, and extra-neuronal restabilization.
mechanisms that could help sustain memory and alter the propen- For example, if inhibiting a specic mechanism disrupts
sity for synaptic destablization, all of which cannot be summarized memory retention after reactivation, but not the induction of recon-
here. However, the involvement of each mechanism for any given solidation, it would be taken as evidence that the mechanism
memory or in any given neuron might be highly variable. Hence, is uninvolved in destabilization but required for restabilization.
systematic identication of the learning conditions that inuence Alternatively, however, inhibiting this mechanism could merely be
the involvement of each is of the utmost importance if we are to insufcient to prevent plasticity initiation, but still be capable of
understand how memories can be stabilized and how new experi- reducing synaptic strength due to weaker signaling. As one exam-
ences can update existing knowledge. ple, endogenous activity of the adrenergic system may facilitate
induction of certain forms of plasticity (i.e. LTP), even if inhibiting
4.6. Converging plasticity pathways? this system does not block plasticity entirely (i.e. LTD; see Yang
et al., 2002 for related ndings). In this way, blocking adrener-
The above discussion is not meant to exclude the possibility gic activity during memory reactivation could likewise reduce the
that there are mechanisms common to most forms of reconsolida- strength of a memory as has been observed for several tasks (i.e.
tion. Plasticity induction mechanisms that vary with training and Debiec and Ledoux, 2004; Przybyslawski et al., 1999) because
reactivation conditions may all converge on shared pathways that it is insufcient to inhibit destabilization entirely. When con-
are important for long-term memory formation and stabilization. sidering the involvement of plasticity mechanisms in behavioral
These points of convergence are not yet clear, so may be best sum- processes, we should be careful to consider how they might inter-
marized in broad terms. For example, most forms of consolidation act or summate to engage plasticity. As a hypothetical example,
and reconsolidation seem to require the synthesis of new proteins two mechanisms (like NMDARs and -adrenergic receptors) have
(Alberini, 2008; Nader et al., 2000; Stoica et al., 2011; though see each been observed to disrupt reconsolidation of spatial memo-
Qi and Gold, 2009 for differing results). This might be involved in ries in hippocampus when inhibited independently (Przybyslawski

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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and Sara, 1997; Przybyslawski et al., 1999, respectively). But if memory loss. Hence we typically avoid discussing the topic of
inhibited together it is conceivable that they might impair plas- age-related memory loss. However, here we raise the relation-
ticity in a manner sufcient to prevent memory destabilization ship of learning-induced metaplasticity to aging because of what
entirely (without impairing retention). We have discussed in Sec- it might tell us about how memories are maintained across the
tion 4.2.4 one example of how simultaneous inhibition of 1 - and lifespan.
-adrenergic receptors (or other GS and Gq coupled receptors) It might be assumed that from birth, experience drives the
could potentially block plasticity entirely (see Huang et al., 2012). encoding of progressively more memories. This should generally
Thus, identifying the specic role of mechanisms in recon- increase the likelihood that any given experience will be similar to
solidation is unlikely to be a straightforward endeavor, as the something that has previously been encountered, and thus might
involvement of each may change with experience and interact with be expected to increasingly recruit memory-updating mechanisms.
other mechanisms in complex ways. In this section we have sim- This could be reected in the mechanisms recruited to encode new
ply presented several mechanisms that we feel are the most likely information in aged versus young adult animals. For example, aging
candidates for the regulation of selective memory stability. is reliably associated with a decline in NMDAR-dependent plas-
ticity both LTP (Boric et al., 2008) and LTD (Kumar and Foster,
2007) and an increase in NMDAR-independent plasticity (Thibault
5. Clinical relevance
and Hadley, 2001). In the rodent hippocampus, this increase in
NMDAR-independent LTP with age has been observed to be medi-
5.1. Suppression of maladaptive memories
ated by L-VGCCs (Shankar et al., 1998). Interestingly, in one study
it was demonstrated that NMDAR-dependent LTP declined with
If destabilization mechanisms were found to change predictably
age, along with behavioral performance at a spatial watermaze
across particular dimensions of training (such as strength of train-
task (Boric et al., 2008). However, NMDAR-independent, L-VGCC-
ing or time since encoding), or due to specic characteristics of a
dependent LTP in hippocampus was observed to be increased
reactivation session (such as presence of reinforcement or length of
in aged rats that had preserved behavioral performance in the
cue re-exposure), this might be advantageous to the clinical appli-
watermaze, while mnemonically impaired aged rats exhibited no
cations of reconsolidation- and extinction-based procedures. The
such increase in L-VGCC-dependent LTP. This was the inverse
former approach involves blocking the restabilization of a memory
pattern exhibited by young rats, for whom NMDAR-dependent
after it is reactivated (see Pitman, 2011), while the latter involves
LTP was positively correlated with better behavioral performance.
enhancing the induction or encoding of an new inhibitory mem-
Based on the ndings that L-VGCCs are necessary for memory
ory trace (Ressler et al., 2004). Drugs applied prior to reactivation
destabilization in the hippocampus (Kim et al., 2011; Suzuki
or extinction could enhance either process, which would often
et al., 2008), this could tenuously indicate that in aged ani-
be expected to have opposite effects on memory expression. For
mals a system of memory updating or overwriting might be
instance, at present a drug like DCS, which enhances NMDAR activ-
recruited to store information via reconsolidation-like mecha-
ity, has been described to facilitate the induction of reconsolidation
nisms, while it might be possible for young animals to more often
(J.L.C. Lee et al., 2009) and enhance the permanence of extinc-
use NMDAR-dependent consolidation mechanisms. This stands
tion training (Walker et al., 2002; Richardson et al., 2004; Mao
at odds with ndings that NR2B-overexpression can rescue age-
et al., 2006). Applied to clinical use, this implies that a failure to
related memory decits in rats and mice (Cao et al., 2007; Clayton
engage extinction processes in a patient may risk destabilizing and
and Browning, 2001). However, the long-term effects of such
strengthening an already debilitating memory. This is further com-
a chronic increase in NR2B expression might be detrimental to
plicated by the lack of an established within-session measure to
memory retention, especially when it is considered that intact
assess whether extinction has been initiated in a patient.
NMDAR activity can actually reduce memory retention over time
To circumvent this problem, the identication of specic
(Villarreal et al., 2002). In this way, reducing NMDAR activ-
molecular targets that preferentially affect the reconsolidation of
ity with age, perhaps via NR2B down-regulation, may preserve
memories of particular strengths, or that could selectively enhance
encoded information, but a switch to L-VGCC-dependent plastic-
reconsolidation induced only by reactivation cues that promote
ity could allow these memory traces to be adaptively modied by
memory weakening could reduce the likelihood of inadvertently
experience.
enhancing memory strength when using these treatments. For
Clearly many other interpretations of these ndings are equally
example, if a mechanism were found to preferentially mediate
valid, but the possibility should not be ruled out that non-
reconsolidation induced by unreinforced reactivation, then a phar-
pathological or even pathological memory impairments during
macological treatment that elevates its activity at memory retrieval
aging are due to the manner in which new experiences are inte-
might help promote destabilization of a traumatic memory such
grated with existing memories. Elevated NMDAR activity could
that it might be weakened therapeutically (i.e. during subsequent
allow for efcient storage of new memories, but might pro-
extinction) or pharmacologically (i.e. by administering an amnes-
mote the decay of older memories. Elevated L-VGCC activity
tic treatment). Designing such approaches will rst require a
could preferentially engage memory updating, and a failure to
better characterization of how different memory destabilization
increase their activity may be detrimental to the encoding of
mechanisms are recruited during various forms of reactivation, as
new information in old animals. We feel that these are important
discussed in Section 4.
considerations for future studies of memory encoding across the
lifespan.
5.2. Aging and memory loss

Given the high prevalence of debilitating memory loss with 6. Conclusions


age, there is often an attempt by researchers to suggest that
mechanisms of memory storage may play a causal role in patho- In the eld of learning and memory we often speak of mem-
logical and non-pathological loss during aging. However, such ory storage systems as though they are xed and permanent. Yet
conclusions may often be unfounded, as almost all mechanisms it is difcult to imagine how a system designed to maintain mem-
involved in memory encoding and maintenance will also be ories in static form could allow widespread remodeling of even
affected during its failure, but it is unlikely that all will initiate the most fundamentally important learned information, such as

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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Fig. 1. A synaptic model of memory destabilization. As a synapse encodes incremental behavioral training the mechanisms initiating plasticity might change, eventually
preventing memory destabilization. (Top) A legend of symbols used. (a) At a naive synapse, behavioral training initiates plasticity by activating basal NMDARs which admit
calcium (perhaps primarily via NR2Bs). Even in a naive synapse this could rst involve destabilizing the existing synaptic structure. Activation of D1/5 receptors may
enhance the activation and expression of NR2Bs. Depolarizations may weakly activate L-VGCCs, which could contribute to this plasticity induction or play a role in synaptic
restabilization by triggering second messengers, gene transcription, etc. CP-AMPARs may be rapidly inserted, as facilitated by PKA activation through D1/5. These channels
could admit large amounts of calcium to the cell to trigger plasticity pathways necessary for memory consolidation. Cholinergic, and adrenergic activity may also promote
plasticity by increasing neuronal excitability. (b) Now that a weak memory has been encoded, a number of changes have occurred at the synapse. The CP-AMPARs inserted
during initial training have likely been replaced by calcium-impermeable (GluR2-containing) AMPARs (Plant et al., 2006). PKM helps maintain these GluR2 AMPARs at
the synapse. Also, some of the NR2B-containing NMDARs have been replaced by NR2A-containing NMDARs. CaMKII now binds to some NR2Bs which might facilitate their
desensitization. Due to interactions with other receptors at the membrane, it could also sensitize nearby NR2As, and help anchor AMPARs to maintain memory. The neuron is
also in a highly excitable state, as mediated by poorly dened regulators of sAHP and mAHP (see Abraham, 2008 for discussion). When this synapse is stimulated during a 2nd
training session, the activation of remaining NR2Bs should induce memory destabilization in amygdala. Longer and stronger depolarization at this potentiated synapse, along
with calcium facilitation via calmodulin, activation of adrenergic receptors, and/or phosphorylation by PKA may enhance L-VGCC activity. In hippocampus this may initiate
destabilization. Note that L-VGCCs and NR2Bs have not been implicated in memory destabilization within the same brain structure, although calcium admitted by both could
potentially facilitate plasticity initiation at a synapse. Although increased calcium inux via L-VGCCs may tend to decrease excitability, other mechanisms (like cholinergic
or adrenergic activity during violations of predictions about the environment), might counteract these effects. This could even decrease post-burst AHP and thus increase
excitability, leading to increased neuronal ring rates. (c) Now that a strong memory has been encoded, many GluR2-containing AMPARs are positioned at the synapse.
The elevated PKM compliment at the synapse could help prevent the synapse from being destabilized during a 3rd training by preventing GluR2 endocytosis, perhaps
even if plasticity mechanisms are engaged. Moreover, NR2Bs have now been mostly replaced by NR2As. Most remaining NR2Bs are persistently bound to CaMKII which
may further inhibit their activity and maintain synaptic structure. When stimulated during a 3rd training session, a lack of novelty (as mnemonic predictions match what
happens during training) causes little dopaminergic, cholinergic, and adrenergic activation. The strong depolarization of this highly potentiated neuron may trigger calcium
inux by L-VGCCs, but this may be rapidly suppressed by voltage and calcium inactivation. Excitability should also have returned to baseline as the task is strongly acquired,
further inhibiting plasticity signals. Some or all of these mechanisms should prevent this strong memory from being destabilized during this 3rd training trial. (d) The synapse
encoding a strong memory is now presented with a reactivation session containing task-related novelty (for example, a new feature in the environment). This should increase
D1/5, -adrenergic, and cholinergic activity to promote plasticity: PKA activation may phosphorylate CP-AMPARs which could promote their expression. These AMPARs may
then mediate considerable calcium inux. Dopaminergic activity may also increase NR2B expression and activity via tyrosine phosphorylation. Adrenergic and cholinergic
activity could also boost neuronal excitability. Together these signals may be sufcient to once again destabilize the strong memory. Although L-VGCC activity would likely
be elevated at this strongly potentiated synapse, it might be rapidly suppressed by voltage or calcium inactivation. As discussed in Section 4.1.3, PKA has not been directly
observed to induce memory destabilization (Tronson et al., 2006). However, it could become a critical step in the destabilization of stronger memories when other plasticity
initiation mechanisms have been suppressed.

that observed in cortical ocular dominance columns of adult ani- very old synaptic connections in the brain may be susceptible to
mals in response to visual deprivation (i.e. Sawtell et al., 2003). experience-dependent plasticity given proper conditions. Deter-
While this could be driven by processes that resemble homeosta- mining how the brain is capable of maintaining some semblance of
sis more than reconsolidation (Goel and Lee, 2007; Mrsic-Flogel stability, and also how this stability can be lifted given appropriate
et al., 2007; though see Ranson et al., 2012), it highlights that even learning situations should be the focus of continued research. This

Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008
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Archbold, Einar Einarsson, Oliver Hardt, and Lara Pierce for their ponents of fear memory formation in the lateral amygdala. J. Neurosci. 22,
insightful comments during the preparation of this review. The 52395249.
Baufreton, J., Garret, M., Rivera, A., 2003. D5 (not D1) dopamine receptors potentiate
authors are funded by grants from NSERC, EWR Steacie, and CIHR.
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Please cite this article in press as: Finnie, P.S.B., Nader, K., The role of metaplasticity mechanisms in regulating memory destabilization
and reconsolidation. Neurosci. Biobehav. Rev. (2012), http://dx.doi.org/10.1016/j.neubiorev.2012.03.008