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Brain Plasticity Mechanisms and Memory: A Party of Four

Elodie Bruel-Jungerman, Sabrina Davis and Serge Laroche
Neuroscientist 2007 13: 492
DOI: 10.1177/1073858407302725

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Brain Plasticity Mechanisms and Memory:
A Party of Four
ELODIE BRUEL-JUNGERMAN, SABRINA DAVIS, and SERGE LAROCHE
Laboratoire de Neurobiologie de l’Apprentissage, de la Mémoire et de la Communication, CNRS, Univ Paris-Sud, Orsay, France

A defining characteristic of the brain is its remarkable capacity to undergo activity-dependent functional and
morphological remodeling via mechanisms of plasticity that form the basis of our capacity to encode and retain
memories. Today, it is generally accepted that the neurobiological substrate of memories resides in activity-
driven modifications of synaptic strength and structural remodeling of neural networks activated during learn-
ing. Since the discovery of long-term potentiation, the role of synaptic strengthening in learning and memory
has been the subject of considerable investigation, and numerous studies have provided new insights into how
this form of plasticity can subserve memory function. At the same time, other studies have explored the con-
tribution of synaptic elimination or weakening; synaptogenesis, the growth of new synaptic connections and
synapse remodeling; and more recently, neurogenesis, the birth and growth of new neurons in the adult brain.
In this review, based on work in the hippocampus, the authors briefly outline recent advances in their under-
standing of the mechanisms and functional role of these four types of brain plasticity in the context of learn-
ing and memory. While they have long been considered as alternative mechanisms of plasticity underlying the
storage of long-term memories, recent evidence suggests that they are functionally linked, suggesting the
mechanisms underlying plasticity in the brain required for the formation and retention of memories are multi-
faceted. NEUROSCIENTIST 13(5):492–505, 2007. DOI: 10.1177/1073858407302725
KEY WORDS Memory, Synaptic plasticity, Long-term potentiation, Long-term depression, Synaptogenesis, Neurogenesis, Hippocampus

The capacity to form, retain, and use memories is a fun-
damental property of the brain essential for survival in all
organisms. For example, an aplysia will learn to withdraw
its gill in response to noxious stimuli; a rodent will learn
to map environments to remember where it can access
food and avoid places in which danger may be apparent.
Humans have a rich array of memories associated with
emotion, acquired skills and habits, facts about life, and
specific episodes of experiences with personal tags.
Collectively, these allow us to form and constantly elabo-
rate our own definition of the world, giving us our indi-
viduality. How do we form memories; how are they
encoded and stored in the brain? The brain is not a passive
recorder of experiences as if information were merely pro-
jected onto a mental screen; it is a dynamic system that
creates information. To process and store a lifetime of
memories, some form of plasticity in the brain that goes
beyond that known to occur during early development is
required. Following Cajal’s original ideas and Hebb’s pre-
scient and influential dual-trace theory, it is now believed
Grant sponsor: Centre National de la Recherche Scientifique. European
Union, Grant RTN-CT-2003-504231 to SL. Ministère de la Recherche,
ACI-NEURO-NIC-0027 to SD. Fellowship from the Fondation pour la
Recherche Médicale to EB-J.
Address correspondence to: Serge Laroche, Laboratoire de Neurobiolo-
gie de l’Apprentissage, de la Mémoire et de la Communication, UMR
8620, CNRS, University Paris-Sud, 91405 Orsay, France (e-mail: serge
.laroche@u-psud.fr).
that memories are encoded as dynamic spatio-temporal
patterns of synchronized cellular activity within wide-
spread neural networks and that this dynamic, reverberat-
ing activity progressively results in altered patterns of
connectivity among the coactivated neurons. Within this
framework, any memory representation would correspond
with specific sets of patterns of activity in overlapping
networks. The neural code embedded within these pat-
terns of activity in large part defies our understanding.
Nonetheless, it has long been recognized that this dynamic
activity, transient in nature, cannot persist long enough to
be the actual substrate of long-term memory. Thus, it has
been postulated that there should exist a second state of
memory encoded as changes at the cellular level to store
these representations. A process of stabilization or consol-
idation would lead to what Hebb called a “structural
trace,” a memory trace that is maintained in some form of
a dormant state but has the capacity to return to an “active
state” to evoke recall whenever a subset of the original
information, or related information, is available. Although
it has been suggested that once a long-term memory had
been established it was stable and remained immune to
any form of disruption, Lewis in 1979 suggested this was
not the case. A so-called established, or consolidated,
memory when reactivated enters a dynamic but fragile
state, requiring further stabilization via synaptic changes
to be available once again for recall, a process now known
as reconsolidation (reviewed in Alberini 2005). The main
point is that long-term memories are not, as was originally

492 THE NEUROSCIENTIST Brain Plasticity and Memory

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thought, stable and essentially “hardwired,” that the mech-
anisms of plasticity in neural circuits that encode and store
long-term memories are dynamic and ongoing throughout
the life of a memory. The function of this form of ongoing
plasticity has not been clarified yet but may well serve to
update or modify existing memories. It is well known that
a single memory over as short a time span of several days
or months evolves as it is incorporated into a vast database
of information.
What are the plasticity mechanisms that serve to store
and update long-term memories? To date, the most widely
held view is that of synaptic strengthening, a process that
occurs during learning whereby memories are stabilized
and stored as modifications of synaptic strength within the
existing neuronal circuits, as originally suggested by Hebb
(1949). The fact that certain neurons possess this property
to undergo activity-dependent synaptic strengthening was
demonstrated by Bliss and Lømo in 1973 when they first
reported their discovery of long-term potentiation (LTP) in
the hippocampus, a brain structure involved in the forma-
tion of many types of memory. To date, there is an enor-
mous amount of data suggesting that, indeed, the type of
synaptic change that is brought about by LTP plays a cru-
cial role in memory formation. There are, however, other
forms of brain plasticity, notably one more recently recog-
nized that is the converse of LTP, long-term depression
(LTD), a form of activity-dependent long-lasting weaken-
ing of synaptic strength. Although physiological evidence
suggests it can be experimentally induced in the same
synapses that can also support LTP, only recently, with the
understanding of the functional effect within the cell that
LTD can induce, has it been envisaged as a potential mech-
anism serving memory processes. Two other forms of
plasticity, synaptogenesis, the growth of new functional
synapses, and neurogenesis, the birth and growth of new
neurons, originally considered to be mechanisms of plas-
ticity restricted to early development, have more recently
been shown to be involved in memory processes in the
adult. Here, we review the advances made in our under-
standing of these four forms of plasticity and their contri-
bution to the formation of long-term memories, focusing
on the hippocampus, and consider whether these different
forms of plasticity act as independent mechanisms or
whether they act together in a concerted manner.
Synaptic Strengthening: Long-Term
Potentiation
Long-term potentiation was first demonstrated in the
rabbit dentate gyrus in 1973 by Bliss and Lømo. They
showed that brief high-frequency stimulation to the per-
forant path, the major input to the hippocampus convey-
ing pretreated information from neocortical areas, leads
to an enduring increase in synaptic strength at dentate
gyrus granule cell synapses (Fig. 1). Since then, some
thousands of reports have followed, demonstrating LTP
is a property shared by neurons in many different corti-
cal and subcortical regions of the brain across different
species, ranging from lizards to humans, and character-
izing the physiological and pharmacological properties
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of LTP and the major cellular and molecular events that
mediate LTP. The physiological and pharmacological
characteristics of LTP that make it a viable mechanism
for learning and memory are that it can be long-lasting,
from weeks to several months, and that it is input-spe-
cific and associative in nature, endowing it with the abil-
ity to process converging input in a manner reminiscent
of associative learning. Shortly after the discovery of
LTP and of some of its underlying molecular mecha-
nisms, many groups exploited this knowledge to charac-
terize the function of this particular property of synaptic
plasticity in the behaving animal. The results of the past
three decades of research have provided strong support
for the idea that the type of synaptic change brought
about by LTP plays a crucial role in memory function
(see Martin and others 2000 for a review). In general,
two main strategies have been used: one is to examine
the “similarity” hypothesis in terms of both the occur-
rence of synaptic changes in certain brain regions during
learning and the activation of biochemical/molecular
mechanisms known to underlie LTP. The second is to
use means to block or enhance LTP and examine the
consequences on learning. Although it has proven a dif-
ficult task, recent studies have provided evidence that
increases in synaptic strength occur in brain during the
formation of memories, for example, in hippocampal
circuits during forms of associative learning that require
an intact hippocampus (Gruart and others 2006;
Whitlock and others 2006) or in the motor cortex during
procedural learning (Rioult-Pedotti and others 1998). In
addition, learning-induced synaptic strengthening was
shown to occlude LTP, suggesting they share common
mechanisms.
The primary mechanism for the induction of synaptic
potentiation in most brain pathways is the activation of a
membrane protein assembly, the NMDA receptor, a slow-
acting, voltage-gated receptor selectively involved in the
induction of LTP (Fig. 2). The NMDA receptor acts as a
coincidence detector requiring two simultaneous events:
the binding of glutamate released from presynaptic bou-
tons and a sufficient level of postsynaptic depolarization
mediated via AMPA receptor activation. When these con-
ditions are met, calcium, the triggering event in LTP,
enters the postsynaptic neuron. Calcium rise is amplified
by the activation of metabotropic glutamate receptors
coupled to G-proteins, which, via the IP3 system, mobi-
lize calcium from intracellular stores locally at the
activated spines (Bliss and Collingridge 1993). The
importance of this mechanism for cognitive function has
been demonstrated in many studies showing that blocking
the NMDA receptor, either pharmacologically or by
genetic inactivation in mutant mice, prevents the induc-
tion of LTP and impairs many forms of learning (e.g.,
Davis and others 1992; Tsien and others 1996).
The NMDA receptor–induced rise in intracellular cal-
cium leads to the activation of numerous synaptic proteins
via posttranslational modification and protein-protein
interaction, constituting the biochemical machinery that
progressively leads to enduring modifications of the
synapse. This is mediated by a complex interplay between
THE NEUROSCIENTIST 493
Fig. 1. Examples of long-term potentiation (LTP) and long-term depression (LTD) in different hippocampal subfields in the
awake rat. A, Schematic diagram of the tri-synaptic circuit of the hippocampus. The hippocampus includes fields CA1-3
and the dentate gyrus (DG). The perforant path (pp) originating from the entorhinal cortex makes “en passant” synapses
with dendrites of the granule cells of the DG. Axons from dentate granule cells, the mossy fibers (mf), contact pyramidal
cells of CA3, and their axons, the Schaffer collaterals (Sch), in turn contact the pyramidal cells of CA1. B, Stable LTP of
perforant path-granule cell synapses of the dentate gyrus induced by brief high-frequency stimulation of the perforant path
(arrow). C, Homosynaptic LTD in area CA1 induced by prolonged, low-frequency pairs of stimuli delivered to Schaffer col-
laterals (arrow). D, The induction of LTP in the dentate gyrus by high-frequency stimulation of the lateral perforant path
(filled circles) is associated with heterosynaptic LTD of the medial perforant path synapses on dentate granule cells (open
circles). EPSP = excitatory postsynaptic potential.

proteins of several signal-transduction cascades (Fig. 2).
The most well characterized of the kinases implicated in
LTP are PKC, PKA, TyrK, CaMKII, PI3K, and the
MAPK/ERK (reviewed in Soderling and Derkach 2000).
Kinases are critical mediators of the early events responsi-
ble for the maintenance or stabilization of synaptic
strengthening, and to date many of these kinases have been
implicated in the consolidation of long-term memories,
reinforcing the idea that LTP-type mechanisms are acti-
vated during learning (e.g., Selcher and others 2002). For
example, numerous experiments have shown that these
kinases are phosphorylated during, or immediately after,
learning and that disrupting the normal activity of
CaMKII, PKA, PKC, PI3K, or MAPK/ERK pharmaco-
logically or genetically generally causes learning and
memory deficits in a variety of tasks. Activation of signal
transduction pathways has two major consequences, the
first being modification of the properties of synaptic recep-
tors; the second being activation of specific genomic pro-
grams. Modification of receptors occurs by phosphorylation
of their subunits, change in the composition of heteromeric
receptors, recruitment of extra-synaptic AMPA receptors
to synaptic sites, and mobilization of the trafficking/recy-
cling machinery to increase the number of AMPA recep-
tors by insertion in the synaptic membrane. The exact
contribution of each of these mechanisms in memory for-
mation is not fully clarified. Recently, however, Rumpel
and colleagues (2005) reported evidence for AMPA recep-
tor trafficking and insertion in synapses of a large fraction
of amygdala neurons following fear conditioning, and
showed this was required for efficient fear memory. Kinase
recruitment of genomic programs in neurons leading to de
novo synthesis of proteins is a critical mechanism for long-
term stabilization of synaptic changes. Known for quite
some time was the fact that inhibitors of transcription or
antibiotics blocking protein synthesis prevent the stabiliza-
tion and therefore maintenance of the longer-lasting
phases of LTP (e.g., Frey and Morris 1997) and that LTP
itself induces the transcription of genes in potentiated neu-
rons. Arguing in favor of the hypothesis that LTP mecha-
nisms are engaged during learning was the demonstration
that the same inhibitors applied during or immediately
after learning prevent long-term, but not short-term, mem-
ory in a variety of tasks and the more recent evidence from
numerous experiments showing that learning is also asso-
ciated with rapid gene regulation in different cell types and
brain regions as a function of the type of task.
How is this genomic response initiated? A critical step is
the expression of a class of immediate early genes (IEGs)
encoding inducible transcription factors, which activate a
host of downstream effector genes to regulate their expres-
sion (Fig. 3). This genomic response generally occurs
within minutes after neuronal activation and is mediated
via kinase-dependent activation of constitutively expressed

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Fig. 2. Schematic representation of the key steps in the molecular mechanisms mediating long-term potentiation in neu-
rons. AA = arachidonic acid; NO = nitric oxide; NOS = nitric oxide synthase; AC = adenylate cyclase; RE = endoplasmic retic-
ulum; mGluR = metabotropic glutamate receptor; PKA = protein kinase; MAPK = mitogen-activated protein kinase; PKC =
protein kinase C; TyrK = tyrosine-specific protein kinase; PI3K = phosphoinositide-3 kinase.

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Fig. 3. Scheme of the main molecular steps involved in synaptic strengthening. Receptor and kinase cascade activa-
tion results in synaptic receptor modification and nuclear transcription of immediate early genes. Some encode synap-
tic proteins, whereas others encode inducible transcription factors such as egr1, which in turn activates transcription of
effector genes, leading to synthesis of the corresponding proteins required for persistent cell modification. Images show
an example of egr1 mRNA overexpression in the dentate gyrus 30 minutes after the induction of LTP, compared to a
control condition (Ct).

transcriptional regulators such as CREB. These activate and
induce the expression of IEGs, the early genomic response
required for triggering the mechanisms underlying persist-
ent cell modification. At present, the best-characterized
molecular cascade involved in synaptic strengthening and
memory consolidation is the MAPK-dependent transcrip-
tional regulation of the IEG Egr1 (also known as Zif268 or
Krox24). Many studies have shown that components of this
cascade such as MAPK/ERK, CREB, and Egr1 itself are
activated in specific brain circuits when animals form dif-
ferent types of memories such as fear memories, olfactory
memories, and memories for specific environments or for
objects (reviews in Sweatt 2001; Davis and Laroche 2006).
Moreover, inhibition of MAPK/ERK, CREB, or inactiva-
tion of Egr1 prevents both the maintenance of synaptic
plasticity and the formation of several types of memories
(e.g., Atkins and others 1998; Jones and others 2001;
Bozon and others 2003). Other IEGs such as BDNF and
Arg3.1 encoding proteins that are not acting as transcrip-
tion factors but are targeted to the synapse also contribute
to synaptic plasticity and memory formation (Lee and oth-
ers 2004; Plath and others 2006). In addition to transcrip-
tional regulation, synaptic modification also involves
protein synthesis from preexisting mRNAs, and mRNAs
trafficked to the dendrites, allowing for rapid and localized
changes at specific synapses. Many genes and proteins
have been shown to be up- and down-regulated in a finely
tuned and coordinated manner in correlation with specific
aspects of LTP and memory processes. Both the full
genomic response of neurons and the synaptic protein sig-
nature resulting from translation of preexisting and newly
transcribed mRNAs that are associated with these
processes are still, however, largely unknown and currently
the subject of intense investigation using newly available
large-scale screening methods.
A recent study adds support to the idea that synaptic
strengthening plays a central role in memory by providing
evidence that the suppression of LTP after learning can
erase a previously established memory (Pastalkova and
others 2006). The authors showed that inhibiting PKMζ,
a kinase involved in the maintenance of LTP, can reverse
or depotentiate LTP, and when injected in the hippocam-
pus even several days after spatial learning, causes retro-
grade amnesia, abolishing the stored memory. This
finding provides strong support to the idea that the main-
tenance of LTP over days is a necessary condition for
the maintenance of memory (see Bliss and others 2006).
To date, compelling evidence suggests that strengthening

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of existing synapses in neural networks, via mechanisms
that endow neurons with the capacity to undergo rapid
and enduring activity-dependent increases in synaptic
weights as exemplified by LTP, is a type of brain plastic-
ity crucially involved in the formation and consolidation
of long-term memories. Despite this evidence, there are
still issues concerning the specific role for LTP mecha-
nisms in processes of encoding and storage of informa-
tion, in different structures and for different types of
memories, that are the subject of intense debate.
Synaptic Elimination/Weakening:
Long-Term Depression
In theory, synaptic elimination, the retraction and disap-
pearance of synaptic connections within complex net-
works, is a means by which synaptic connections can be
lost. Based on the “use it or lose it” rule, the undoing or
loss of connections may reflect a mechanism for forget-
ting or retrieval failure; alternatively, it may serve a means
to weaken unused connections, thereby promoting the
emergence of patterns of reinforced connections in the
network, a selection process that could potentially be an
advantage for information storage. Synaptic elimination
or pruning is a property of the brain known to play a cru-
cial role in specifying wiring of neural circuits during
development. Recent evidence suggests synapse elimina-
tion can play a role in learning. One example is the selec-
tive, NMDA receptor–dependent elimination of spine
synapses after auditory filial imprinting in the juvenile
chicken (Bock and Braun 1999). Nevertheless, there is as
yet little if any evidence that true synapse elimination
could play a role in cognitive functions in the adult.
Functionally, however, the discovery that activity-dependent
LTD of synaptic efficacy can occur at hippocampal
synapses under certain conditions of stimulation (e.g.,
Dudek and Bear 1993) indicates that neurons have the
mechanisms to trim down synaptic strength in a form that
can be functionally equivalent to synaptic elimination or
selection. Reduction of synaptic weights can take several
forms: de novo LTD, an activity-dependent depression at
“naive” synapses; depotentiation, corresponding to rever-
sal or erasure of LTP; and heterosynaptic LTD, the weak-
ening of synaptic strength at nonactive synapses in
association with potentiation of other neighboring
synapses (Fig. 1). Research into the mechanisms and
functional role of LTD has long been hampered by the dif-
ficulty to find reliable stimulus protocols for its induction
in the adult brain in vivo. However, it can readily be
induced in the juvenile, which is more likely to have little
history of environmental experience or synaptic modifica-
tion, suggesting LTD may play a more important role
during development for the refinement of synaptic con-
nectivity. LTD can, however, be observed in the adult in
vivo under certain conditions in CA1 (Thiels and others
1994; Doyère and others 1996) and in the dentate gyrus
(Kemp and Manahan-Vaughan 2007). In contrast, depo-
tentiation and heterosynaptic LTD can be observed more
reliably in the adult in vivo in many different brain struc-
tures and conditions, including long low-frequency trains
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of stimulation, electroconvulsive shock, stress, and novel
environmental conditions.
Mechanisms of LTD in hippocampal areas are diverse.
NMDA-dependent LTD requires a rise in calcium as in
LTP, but the “decision” as to whether LTP or LTD is
induced seems to depend on the amplitude, kinetics, and
localization of calcium influx. With a marked and rapid
rise, LTP is induced, but with a modest and more lasting
increase favoring the activation of phosphatases rather
than kinases, LTD ensues. This dissociation between
the signaling events mediating NMDA-dependent LTP
and LTD seems to reflect the activation of receptors con-
taining different NR2 subunits and synaptic location
(Collingridge and others 2004). Some forms of LTD,
however, that depend on group I mGluRs, have a strong
presynaptic component and involve tyrosine phosphatases
and the MAPK and PI3K-Akt-mTOR cascades. Although
the signaling mechanisms of these different forms of LTD
require clarification, recent studies suggest that key mech-
anisms underlying the expression of LTD include dephos-
phorylation of specific residues on GluR1-containing
AMPA receptors, lateral diffusion to extrasynaptic sites,
and internalization of AMPA receptors (Beattie and others
2000; Collingridge and others 2004). Protein synthesis is
also involved in certain forms of LTD.
At present, it is unclear whether LTD per se has a role
in learning and memory as a cellular storage mechanism
or whether this form of plasticity merely serves to adjust
or counterbalance synaptic strengthening. There are
some indirect arguments in favor of the first hypothesis.
For example, in the cerebellum, a brain structure in
which both LTD and LTP phenomena have been
observed but LTD seems to be the dominant form of
plasticity, there is a great deal of evidence to suggest that
LTD mechanisms are implicated in forms of motor and
associative learning for which this structure is essential
(reviewed in De Zeeuw and Yeo 2005). In the hip-
pocampus, a recent study has shown that LTD can be
induced by low-frequency stimulation when rats explore
novel environments with objects, but not when this envi-
ronment has become familiar, suggesting a role for LTD
in complex spatial mapping (Kemp and Manahan-
Vaughan 2007). Furthermore, impairment of hippocam-
pal LTD, with no apparent alteration in LTP, has been
observed in mutant mice with forebrain-specific deletion
of serum response factor, an enhancer site for the expres-
sion of many IEGs. These mice display selective deficits in
memory for novel contexts in association with decreased
expression of serum response element–containing genes
including Egr1- and LTD-related genes (Etkin and oth-
ers 2006). The authors suggest that LTD-like mecha-
nisms occurring during memorization of a novel context
may endow synapses with a greater potential to undergo
LTP-like strengthening during their subsequent recruit-
ment when the animal learns an explicit memory related
to that context.
As most modifiable synapses in the brain can support
both LTP- and LTD-like mechanisms, a possible key
role of LTD in brain function could be to maintain the
overall synaptic drive in a network constant, a process
THE NEUROSCIENTIST 497
referred to as synaptic scaling. Most neural network
models incorporate homeostatic processes to prevent
saturation of the system and a potential block of its stor-
age capacity. Experimental evidence suggests that satu-
rating LTP in a restricted cell population results in the
inability to form new associative memories (Moser and
others 1998). Bidirectional plasticity demonstrates a
mechanism whereby synaptic strengthening and weak-
ening can occur instantaneously and simultaneously at
different synapses on a neuron or in different neurons in
a given circuit, preventing chronic excitation of popula-
tions of cells that could cause dysfunction. To date, it is
reasonably well established that one key mechanism of
bidirectional plasticity is activity-dependent regulation
of cell surface expression of AMPA receptors, with
LTP associated with insertion and LTD with internal-
ization of AMPA receptors (Collingridge and others
2004). There is physiological evidence for homeostatic
responses to neural activity, for example, in the develop-
ing cortex, when visual activation is increased, stimulat-
ing frequencies that normally induce LTP but either no
longer do so or induce LTD. Conversely, visual depriva-
tion promotes LTP over LTD (Perez-Otano and Ehlers
2005), and prolonged inhibition of cells can lead to an
increase in AMPA-mediated currents (Turrigiano and
others 1998). Prolonged or high activation can reduce
trafficking of NR1 subunits, whereas blocking neuronal
activity increases trafficking (Perez-Otano and Ehlers
2005). In the adult mouse visual cortex, environmental
conditions can induce long-term homeostatic regulation
to switch plasticity from synaptic weakening to strength-
ening (Yashiro and others 2005). Finally, heterosynaptic
depression may be essential for constraining synaptic
plasticity and maintaining cell function within a physio-
logical range while allowing locally induced synaptic
strengthening. In the dentate gyrus, for example, induc-
tion of LTP at one subset of synapses is always associ-
ated with LTD at other synapses on the same neurons
(Doyère and others 1997). Evidence also suggests that
the maintenance of LTP at a given input can be unstable
and subject to dynamic modification by ongoing activity
of neighboring synapses (Fonseca and others 2004). As
described below, other means of preventing saturation of
synaptic plasticity associated with memory could
include remodeling of connectivity patterns via mecha-
nisms such as synaptogenesis and neurogenesis.
Synaptogenesis and Synapse Remodeling
Although it has long been speculated that structural
rearrangements and remodeling of neural networks could
be a prime candidate mechanism underlying the persist-
ence of memories, a long-standing issue is whether the
cellular mechanisms of memory lead to true synaptogen-
esis, the growth of new synapses, or merely to morpho-
logical remodeling of existing synapses. In development,
synaptogenesis occurs over a protracted period starting
during embryogenesis and extending in the postnatal
period to about day 90 in the rodent’s hippocampus. The
process is mediated by cell-cell interactions that control
498 THE NEUROSCIENTIST
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different cellular processes in a highly orchestrated hier-
archical sequence of events that mediate the competence,
placement, composition, size, and stability of functional
synapses (Waites and others 2005). Many molecules,
including adhesion molecules such as the CAMs of the
cadherin and protocadherin superfamilies, SynCAM and
neuroligin, serve as recognition sites or act to confirm cor-
rect positioning and initiate contact, whereas others such
as β-neurexin, NARP, and EphrinB are involved in
recruitment of glutamate receptors and postsynaptic scaf-
folding proteins. Neuronal activity is implicated in regu-
lating the stability of the nascent synapse, with activity of
intracellular signaling pathways and trafficking of pro-
teins exerting tight control over morphological and phys-
iological maturation of the new synaptic contacts. In
the adult, reactive synaptogenesis is often observed in
response to denervation, suggesting sprouting of axon
collaterals and growth of new synapses to occupy vacated
sites.
In the adult, the search for learning-induced increases
in synapse number has proven a difficult task and has led
to conflicting results. Some indirect arguments come from
studies showing modulation of synapse number by hor-
mones or stress in a manner that correlates with learning
abilities. Living in enriched environments has also been
reliably found to result in dendritic expansion and
increased spine and synapse numbers, and histological
analyses have shown changes in synapse number after
certain learning paradigms (reviewed in Markham and
Greenough 2004). A clear example is the NMDA-dependent
increase in spine density observed in CA1 of the hip-
pocampus 24 hours after training rats in a hippocampal-
dependent form of associative learning (Leuner and oth-
ers 2003), or the finding of increased spine density in the
amygdala after fear conditioning (Radley and others
2006). Several other studies, however, failed to find an
overall increase in synapse number after learning,
although many aspects of synapse restructuring were
observed in a consistent manner (see Geinisman 2000).
Difficulties associated with structural analyses ex vivo
include the impracticality to analyze time-courses of
changes in a dynamic manner and to ascertain which neu-
rons and synapses have been active or strengthened dur-
ing learning. In addition, finding no change in the overall
synapse density in a given structure does not exclude the
possibility for increased density of certain types of spines
at the expense of others, or homeostatic processes with
increases and decreases in different portions of dendrites
or in different neurons (e.g., Rusakov and others 1997;
Harris and others 2003). A similar picture emerges with
LTP, where there is little evidence to suggest that the over-
all number of synapses per neuron change with LTP,
although localized outgrowth of filopodia-like protrusions
from dendrites in the immediate vicinity of potentiated
synapses occurs (Marrone and Petit 2002).
Several types of morphological changes at existing
synapses have, however, been observed after LTP and after
learning (reviews in Geinisman 2000; Harris and others
2003). They include changes in synapse curvature, in size
of the active zone and spine volume, increases in synaptic
Brain Plasticity and Memory
length, and the appearance of perforations of the synapses
and multiple-synapse boutons where one presynaptic ter-
minal makes contact with distinct postsynaptic spines. In
contrast, LTD has been reported to induce spine shrinkage
(Zhou and others 2004). Modification of the morphologi-
cal characteristics of the synapse appears, in general, to
follow a sequential order of events that lead to an increase
in synaptic efficacy. In hippocampal LTP, for example,
there appears first to be a change in the curvature of the
synapse showing an increase in the proportion of concave
over convex synapses that occurs between 2 minutes and
24 hours following induction of LTP. Although it is unclear
what determines the shape of the synapse, it has been sug-
gested that concave synapses may be induced by an
increase in the size of the presynapse caused by increased
transmitter release that forces the postsynapse to curve
around it, and by the breakdown of actin filaments in the
postsynaptic density (PSD) causing the change postsynap-
tically. The outcome is to draw the receptors closer to the
synaptic cleft, thereby increasing the potential for the post-
synapse to be activated. This change in curvature may last
no longer than five days following the induction of LTP,
with a tendency for synapses to return to a convex shape,
suggesting that repeated activation may be required to
maintain lasting changes. A second form of reorganization
is the appearance of perforated synapses with a discontin-
uous PSD resulting from the disassembly of adhesion mol-
ecules that span the synaptic cleft. It has been suggested
that perforations and progressive partition could be an
intermediary event prior to synapse splitting, giving rise to
two morphologically separated synapses (Luscher and oth-
ers 2000). Synapse splitting, however, has not been reli-
ably observed, at least shortly after LTP (Harris and others
2003). In the hippocampus, electrophysiological evidence
suggests there are “silent” synapses, containing NMDA
but not AMPA receptors; however, LTP has been shown to
convert silent synapses to AMPA-containing, active
synapses (Isaac and others 1995; Liao and others 1995).
The appearance of perforated synapses is associated with
an increased expression of AMPA receptors and might be
a morphological correlate of this conversion, leading to
several independent transmission units (Geinisman 2000).
The appearance of perforated synapses maintaining com-
partmentalized units may also enable more efficient
cycling of receptors in and out of the membrane and the
shuttling of receptors between the extra-synaptic and
active zones of the synapse (Marrone and Petit 2002).
Thus, in all, both the induction of synaptic plasticity and
learning can induce remodeling of neural circuits either
through de novo synaptogenesis or a range of morpholog-
ical changes that can lead to increased synaptic strength
and the appearance of new functional units, including
branching spines and multisynaptic boutons, together with
the functional conversion of silent to active synapses. It is
clear, however, that full characterization of these changes
after learning in different structures and in relation to dif-
ferent forms of memory requires further investigation.
Marrone (2007), conducting a meta-analysis of structural
changes after hippocampal-dependent learning, concluded
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that among the most reliable changes observed are a large
increase in the density of multisynaptic boutons, particu-
larly in CA1; increased spine density; and increased size
and density of perforated synapses, mostly in CA3 and the
dentate gyrus. The analysis also revealed a greater propen-
sity for cortical areas to display learning-related increases
in spine density than hippocampal areas, whereby the hip-
pocampus may be more subject to homeostatic changes.
This suggests that morphological changes induced by
learning may differ in a regional-specific manner.
Neurogenesis
Contrary to the traditional dogma that neurogenesis, the
birth and growth of new functional neurons, is a strictly
developmental phenomenon, Altman (1962) was the
first to suggest that new neurons continue to be added to
the adult brain throughout life. This is now clearly estab-
lished in different species (reviewed in Gross 2000),
including in humans (Eriksson and others 1998). In the
mammalian brain, adult neurogenesis is to date thought
to be confined to the dentate gyrus of the hippocampus
and olfactory bulb, although it may occur in other brain
regions in conditions of brain damage. Adult neurogen-
esis is a slow process that involves proliferation of pro-
genitor cells, commitment to a neuronal phenotype,
morphological and physiological maturation with the
development of functional neuronal characteristics, and
synaptic integration into existing neural networks. In the
dentate gyrus (Fig. 4), neural progenitor cells located in
the subgranular zone give rise to transient amplifying
progenitors that in turn differentiate into new immature
neurons and migrate locally into the granular cell layer
where they mature into dentate granule cells. They
receive synaptic inputs from entorhinal cortex neurons
via the perforant path and extend their axons to estab-
lish synapses onto CA3 pyramidal cells, thus becoming
functionally integrated into cortico-hippocampal cir-
cuitry (reviews in Ming and Song 2005; Bruel-Jungerman
and others 2007). Although thousands of new neurons
are born each day, a large proportion, will not complete
maturation and die by apoptosis within the first few
weeks (Kempermann and others 2003). Several factors
can regulate neurogenesis and influence the destiny of
newborn cells, promoting either their survival or death.
These include nearly all neurotransmitters, hormones,
and growth factors, as well as epigenetic factors and
extrinsic/environmental factors such as stress, social iso-
lation, drug abuse, alcohol consumption, and aging as
negative regulators, and physical exercise, environmen-
tal enrichment, and learning as positive regulators
(reviews in Abrous and others 2005; Ming and Song
2005).
What the contribution of neurogenesis to cognitive
functions is and whether it provides another mechanism
of plasticity subserving learning and memory are still a
matter of debate. In a series of studies, Gould and col-
leagues (1999) demonstrated that types of learning that
depend on the integrity of the hippocampus, including
THE NEUROSCIENTIST 499
Fig. 4. Neurogenesis in the dentate gyrus. Top, an example of BrdU-labeled newly generated cells in the granule cell layer
(gcl) of the dentate gyrus. The birthdating marker BrdU labels mitotically active cells (dark) on sections counterstained with
nuclear fast red to label dentate granule cells (pink). Bottom, Confocal laser microscopic images of immunostained sec-
tions showing co-localization of BrdU (red) with the neuron-specific marker NeuN (green). Bottom images reprinted with
permission from Bruel-Jungerman et al. 2006. Longterm potentiation enhances neurogenesis in the adult dentate gyrus.
J Neurosci 26:5888–93. Copyright 2006 by the Society for Neuroscience.

spatial learning in the water-maze and trace eye-blink
conditioning, enhance the survival of 1-week-old new-
born neurons in adult rats, whereas no effect was found
after learning tasks that do not require an intact hip-
pocampus. These findings suggest that learning can res-
cue young neurons from death. Several studies confirmed
the pro-survival effect of hippocampal-dependent learn-
ing (e.g., Lemaire and others 2000; Leuner and others
2004), but others reported no change or sometimes a
decrease in neurogenesis (van Praag and others 2000;
Olariu and others 2005; Snyder and others 2005). Reasons
for these contrasting results are not fully clarified,
although several variables may account for the discrepan-
cies, including differences in learning paradigms and the
degree of physical activity and stress induced, and the age
and maturation of the cells at the time of learning (reviewed
in Bruel-Jungerman and others 2007). Overall, however,
it seems reasonable for the time being to conclude that
certain types of hippocampal-dependent learning can pro-
mote hippocampal neurogenesis and that this is sensitive
to task difficulty and hippocampal demand. Under these
conditions, learning can rescue young neurons from
death, perhaps by increasing activity-dependent integra-
tion of immature neurons. Moreover, a recent study ana-
lyzing learning-induced gene expression in young
newborn neurons provided evidence that these neurons
are recruited into the circuits involved in spatial memory
(Kee and others 2007).
If neurogenesis plays a role in learning and memory,
then disruption of neurogenesis is likely to result in
impaired cognitive performance. Again here, an influential
study showed that experimental reduction of neurogenesis
in the adult impairs trace eye-blink conditioning but not
hippocampal-independent delay conditioning (Shors and
others 2001). The deleterious effect of neurogenesis reduc-
tion or blockade has been observed in several other tasks,
including contextual fear conditioning, some forms of spa-
tial learning, and performance in working memory tasks
(e.g., Madsen and others 2003; Saxe and others 2006;
Winocur and others 2006), with the exception of spatial
learning in the water-maze (Shors and others 2002), where
neurogenesis seems to be involved in long-term storage

500 THE NEUROSCIENTIST Brain Plasticity and Memory

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rather than acquisition of spatial information (Snyder and
others 2005). Thus, at present it seems that new young
neurons in their first few weeks are an advantage for the
acquisition and/or the consolidation of long-term memory
of certain types of learning, in particular, when learning
imposes a high hippocampal demand on a relational mem-
ory system for associating events in space and/or time.
Several other studies also provide a strong correlative
link between hippocampal neurogenesis and cognitive
abilities. For example, housing adult animals in com-
plex, enriched environments where they have opportuni-
ties for learning and for interacting socially is known to
improve learning and memory abilities. This is associ-
ated with increased hippocampal neurogenesis (Fig. 5),
and the new neurons produced during enrichment were
shown to be crucial for the improvement of the capacity
to store new information in long-term memory (Bruel-
Jungerman and others 2005). Neurogenesis during
enrichment does not seem, however, to be required for
enrichment-induced facilitation of spatial learning
(Meshi and others 2006), suggesting either a task speci-
ficity or a primary involvement of young neurons in con-
solidation rather than acquisition of new information.
Enrichment also promotes synaptogenesis in various
hippocampal areas, including in dentate gyrus and CA3
target cells (reviewed in Markham and Greenough
2004), an effect that might well be a consequence of the
increased number of surviving, functionally integrated
newborn neurons after enrichment. Thus, neurogenesis
appears to be another mechanism of plasticity involved
in memory functions. New neurons may in fact serve
several functions depending on their birth date and age:
Those that are coming to the brink of their maturation
stage at the time of learning might be directly involved
in the learning and memory process at hand, whereas
more immature ones and those that will mature after
learning may serve as a pool of “naive” neurons that
could be both beneficial for later learning experiences
and detrimental for remembering past experiences
(Bruel-Jungerman and others 2007).
How can newborn neurons participate to memory
processes? The functional relevance of immature adult-
generated neurons seems to rely on the particular physi-
ological properties they have, making them particularly
inclined to undergo activity-dependent plasticity.
Several recent reports have highlighted their high
excitability and sensitivity to synaptic plasticity. They
show that young dentate gyrus neurons have a lower
threshold for LTP induction and produce stable LTP
more readily than more mature neurons (Snyder and oth-
ers 2001; Saxe and others 2006), presumably due to the
specific membrane properties observed in one- to three-
week-old cells, greater NMDA receptor sensitivity and
calcium entry upon synaptic activation (Schmidt-Hieber
and others 2004). As a functional readout of this, neuro-
genic factors such as environmental enrichment and
physical exercise, which promote neurogenesis and
improve memory abilities, also facilitate LTP in the den-
tate gyrus (van Praag and others 2000; Duffy and others
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2001). Overall, these findings strongly suggest that the
addition of new neurons translates into changes in net-
work properties, increasing the computational capacity
of the circuits within which they are embedded.
Moreover, newly generated naive neurons appear to be
particularly suited to respond to, and integrate informa-
tion coming from, cortical afferents to the hippocampus,
providing a cell population particularly well adapted for
recruitment during the formation of new memories.
Direct evidence also points to another, unsuspected
link between LTP and neurogenesis: that the occurrence
of LTP enhances the rate of hippocampal neurogenesis
(Bruel-Jungerman and others 2006). This study showed
that the induction of LTP in the dentate gyrus increases
the proliferation of new neurons and results weeks later
in a larger population of surviving new neurons.
Moreover, when LTP impinges on young, recently born
neurons aged one to two weeks, they have a much higher
probability of survival (Fig. 6). Thus, LTP in the dentate
gyrus can both increase the production of new neurons
and promote survival of young neurons. The underlying
mechanisms may involve NMDA receptor activation, as
it was shown that (1) excitatory stimuli can act directly
on progenitor cells to favor neuronal production in an
NMDA receptor–dependent manner (Deisseroth and
others 2004) and (2) that, during a critical period soon
after birth, survival of new neurons is competitively reg-
ulated by their own NMDA receptors (Tashiro and oth-
ers 2006). It is also possible that LTP at surrounding
mature cells provides a cellular/molecular microenviron-
ment that favors cell proliferation and the survival of
recently born neurons, perhaps via the release of neuro-
transmitters and/or growth factors. In any case, the
demonstration that LTP promotes neurogenesis presents
the intriguing hypothesis that the occurrence of activity-
dependent synaptic plasticity in the dentate gyrus during
learning may provide signals involved in learning-
induced neurogenesis.
Conclusion
In this brief review, we have outlined four candidate
mechanisms of plasticity in the brain that appear to be
essential for forming and retaining memories. Research
over the past decades has clearly established that neural
circuits in the brain undergo continuous, dynamic mod-
ification in relation to learning and memory formation,
in the form of synaptic strengthening and weakening,
synapse formation and remodeling, and neurogenesis.
Our current understanding of the role of these mecha-
nisms of plasticity in the laying down of memories
departs from the early conceptual thinking as alternative
solutions to the problem of the cellular mechanisms of
memory, toward the emerging idea that they act as asso-
ciate partners, even if the exact functions of each of
these mechanisms are not yet fully clarified. Empirical
data so far have considerably strengthened the case for
synaptic strengthening via mechanisms exemplified by
LTP as a critical feature of memory consolidation, pro-
THE NEUROSCIENTIST 501
Fig. 5. The contribution of neurogenesis to memory function. A-D, Environmental enrichment increases neurogenesis
in the dentate gyrus, and the antimitotic drug MAM reduces neurogenesis. Images show a larger number of BrdU-
immunostained labeled newly born cells in the dentate gyrus of rats exposed to enriched environments for 3 hours a
day for 14 days (a, c), compared to rats receiving MAM during enrichment (b, d). Bottom, Environmental enrichment
increases the ability of rats to form a long-term memory of objects that they have briefly been exposed to before the
test (red triangles), compared to control rats (open circles), which can form short-term but not long-term recognition
memory. Rats injected with an antimitotic drug to stop neurogenesis during enrichment do not benefit from enrichment
(green triangles). Thus, the birth of new neurons is a crucial plasticity mechanism subserving the improved capacity to
memorize objects. gcl = granule cell layer; sgz = subgranular zone. Adapted from Bruel-Jungerman E, Laroche S,
Rampon C. 2005. New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory fol-
lowing environmental enrichment. Eur J Neurosci 21:513–21.

viding evidence that the type of synaptic change that is foresee in the context of learning and memory in the
brought about by LTP is an essential mechanism to store adult; however, synaptic weakening, a form of “functional
memory representations and leads to retrievable memo- elimination,” also appears critical, if not as a cellular
ries. True synaptic elimination as yet is more difficult to storage mechanisms per se then at least as an essential

502 THE NEUROSCIENTIST Brain Plasticity and Memory

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Fig. 6. Long-term potentiation promotes proliferation and survival of newly born dentate granule neurons. A, The induc-
tion of LTP at perforant path-dentate gyrus synapses increases the proliferation of newly generated cells in the dentate
gyrus. Representative sections immunostained for BrdU (dark) with nuclear fast red counterstaining (pink) were obtained
24 hours after BrdU was injected on day 4 after LTP induction. B, LTP also promotes the survival of young new neurons
born one or two weeks before LTP induction. In this case, BrdU was injected and LTP induced 2 weeks later.
Immunostained sections were obtained four weeks after BrdU injection. C, A significant fraction of these young neu-
rons express the IEG egr1 (zif268) in response to LTP. Confocal laser microscopic images of double-immunostaining for
BrdU (red) and Zif268 (green) 2 hours after LTP induction. Reprinted with permission from Bruel-Jungerman et al. 2006.
Long-term potentiation enhances neurogenesis in the adult dentate gyrus. J Neurosci 26:5888–93. Copyright 2006 by
the Society for Neuroscience.

homeostatic mechanism for fine-tuning of neural con-
nectivity. Similarly, important advances have been made
in strengthening the idea that synaptogenesis, morpholog-
ical and functional synapse remodeling, and neurogenesis
in certain brain regions are key mechanisms underlying
structural shaping of neural connectivity in the process of
memory stabilization.
The evidence as broadly outlined here suggests these
four mechanisms of plasticity are not completely inde-
pendent. Synaptic strengthening, demonstrated by LTP,
is often associated with LTD at neighboring synapses;
LTD modifies the capacity for LTP, and LTP modifies
the capacity for LTD. The induction of LTP progres-
sively induces functional and structural reorganization of

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synapses and synaptic growth, whereas LTD can induce
shrinkage of synapses. Finally, the activity-dependent
maturation and stabilization of new neurons during adult
neurogenesis, associated with synaptic outgrowth, results
in an increased capacity for LTP, and LTP itself promotes
proliferation and survival of newborn neurons. Thus,
these four types of plasticity appear to act as partners in
a multifaceted mechanism to create specific neural net-
works during the laying down of memories, even if they
may retain specific, independent functional contributions
to memory function, in particular, in relation to the tem-
poral dynamics of memory processes. Importantly, if the
four types of plasticity are implicated in memory func-
tion, a high degree of structure specificity in their
involvement is apparent. The clearest example is with
adult neurogenesis, which under normal conditions is
restricted to only a few brain structures and therefore
cannot be regarded as a general “learning device.” Other
types of structure specificities have been outlined, for
instance, the apparent higher propensity of cortical
regions to undergo learning-dependent synaptogenesis.
Key issues for the future are now to define precisely in
which condition, phase, or process of learning and mem-
ory these four types of brain plasticity are involved and
which structures and neural circuits express these mech-
anisms in relation to different types of memories. As a
final note, the contribution of these four types of plastic-
ity to memory function is further highlighted by the
emerging evidence that dysfunctional mechanisms of
plasticity are, in large part, responsible for deficient
memory that occurs with aging and for a wide range of
pathological disorders including neurodegenerative, neu-
rological, and psychiatric diseases.
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