Neuropharmacology 206 (2022) 108922

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Neuropharmacology
journal homepage: www.elsevier.com/locate/neuropharm

Glutamate receptors and synaptic plasticity: The impact of Evans

and Watkins
G.L. Collingridge a, b, c, *, W.C. Abraham a
a
Department of Psychology, Brain Health Research Centre and Brain Research New Zealand, University of Otago, New Zealand
b
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada
c
TANZ Centre for Research in Neurodegenerative Diseases, Department of Physiology, University of Toronto, Toronto, ON, Canada

A R T I C L E I N F O A B S T R A C T

Keywords: On the occasion of the 40 year anniversary of the hugely impactful review by Richard (Dick) Evans and Jeff
LTP Watkins, we describe how their work has impacted the field of synaptic plasticity. We describe their influence in
LTD each of the major glutamate receptor subtypes: AMPARs, NMDARs, KARs and mGluRs. Particular emphasis is
Hippocampus
placed on how their work impacted our own studies in the hippocampus. For example, we describe how the tools
NMDA receptor
Metabotropic glutamate receptor
and regulators that they identified for studying NMDARs (e.g., NMDA, D-AP5 and Mg2+) led to the understanding
D-AP5 of the molecular basis of the induction of LTP. We also describe how other tools that they introduced (e.g.,
Magnesium (1S,3R)-ACPD and MCPG) helped lead to the concept of metaplasticity.
MCPG This article is part of the Neuropharmacology Special Issue on ‘Glutamate Receptors – NMDA receptors’.

1. Introduction
Understanding the mechanisms of synaptic plasticity has been one of
the major challenges in science as this process underlies learning and
memory and other cognitive functions within the animal kingdom.
Considerable progress has been made by the collective work of many
individuals globally and a wide range of experimental approaches have
been employed. Much of this information, particularly in the early years,
has been gained through the careful application of neuropharmacology,
in particular in the area of glutamate receptors. In this article, which is
part of this Special Issue to commemorate the impactful review article
published 40 years ago by two of the glutamate receptor pioneers,
Richard (Dick) Evans and Jeff Watkins (Watkins and Evans, 1981), we
focus on how their developments in glutamate receptor pharmacology
have impacted the field of synaptic plasticity. A detailed account of the
many contributions by the large number of research groups around the
world who have used these tools in the study of synaptic plasticity is
beyond the scope of this article. Rather, the purpose of this article is to
use primarily our own research, plus a few selected examples from other
laboratories, as examples to illustrate the impact the work of Evans and
Watkins has had, and continues to have, in the field of synaptic plasticity
on the occasion of the 40th anniversary of their hugely influential re­
view article. For fascinating insights into the earlier work of Jeff Watkins
with David Curtis, that set the scene for what we describe here, as well as
for the broader impact of the work originating in the Bristol Pharma­
cology Laboratory the reader is referred to the personal reflections of
Watkins and Jane (2006).

* Corresponding author. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON, Canada.
E-mail address: collingridge@lunenfeld.ca (G.L. Collingridge).

https://doi.org/10.1016/j.neuropharm.2021.108922
Received 27 August 2021; Received in revised form 23 November 2021; Accepted 9 December 2021
Available online 15 December 2021
0028-3908/© 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
G.L. Collingridge and W.C. Abraham
2.1. AMPA receptors
2.1.1. AMPA receptors - discovery
Watkins developed some of the first generation antagonists that
acted at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid re­
ceptors (AMPARs) and kainate receptors (KARs).1 In particular, he
synthesized γ-D-glutamylglycine (DGG) and cis-2,3-piperidine dicar­
boxylate (PDA) and used these to present evidence that AMPA/KARs
mediate synaptic transmission in the CNS (Watkins and Evans, 1981).
His collaborators, notably the late John Davies, found that these com­
pounds depressed fast monosynaptic excitation in the spinal cord.
Although PDA and DGG are also NMDAR antagonists, more specific
NMDAR antagonists did not affect this synaptic response. This therefore
provided some of the most direct evidence that AMPARs mediate fast
synaptic excitation in the vertebrate CNS.
2.1.1. AMPA receptors - role in synaptic plasticity
We (GLC) tested the same antagonists on the monosynaptic
connection between CA3 and CA1 neurons in the hippocampus, the
Schaffer collateral - commissural pathway (hereafter referred to as CA3-
CA1 synapses) (Collingridge et al., 1983a). We also observed a synaptic
depression that was not mimicked by selective NMDAR antagonists. The
distribution of AMPARs and KARs in the hippocampus suggested that
this effect was most probably due to antagonism of AMPARs (Monaghan
and Cotman, 1982; Monaghan et al., 1984). Since then, the development
of more potent and more selective AMPA antagonists, such as the qui­
noxazalinediones (Honoré et al., 1988), the GYKI compounds (Tarnawa
et al., 1989) and perampanel (Hibi et al., 2012), a compound used
clinically for the treatment of seizures, have established beyond any
doubt that fast synaptic transmission at this synapse is mediated by
AMPARs (e.g., Blake et al., 1988; Andreasen et al., 1989; Ceolin et al.,
2012). The use of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)
enabled us to demonstrate directly that long-term potentiation (LTP)
involves an increase in AMPAR-mediated synaptic transmission (Davies
et al., 1989). Since AMPAR-mediated synaptic transmission is enhanced
during LTP and depressed during long-term depression (LTD; see Col­
lingridge et al., 2004, 2010), these receptors can be considered as
“memory receptors”, mediated the long-lasting alterations in synaptic
efficacy.
Although DGG has been superseded by more potent and more se­
lective AMPAR antagonists, its low affinity for AMPARs has proven
useful in probing for changes in the amount of L-glutamate released at
synapses (e.g., Chamberland et al., 2014; Kirk et al., 2017).
2.2. NMDARs
2.2.1. NMDA receptors - discovery
To understand how L-glutamate and L-aspartate interacted with its
receptor(s), Jeff Watkins decided to synthesize structurally constrained
analogues of these naturally occurring amino acids. One of the first
1
Footnote: A variety of terminologies have been used historically to describe
what are now referred to as NMDA, AMPA and KA receptors. For example,
glutamate-preferring, non-NMDA, AMPA/kainate and quisqualate receptors are
names given to what are now universally called AMPARs. Here we adopt the
accepted nomenclature of NMDA, AMPA and KA for the three main classes of
ionotropic glutamatergic receptors. These are the heteromeric assemblies of
four subunits drawn from: NMDARs - GluN1, GluN2A, GluN2B, GluN2C and
GluN2D subunits (GluN3 subunits can co-assemble with these subunits but are
not discussed in the present article), AMPARs: GluA1, GluA2, GluA3 and GluA4,
KARs: GluK1, GluK2, GluK3, GluK4 and GluK5, respectively. Note that these are
the IUPHAR approved names for the subunits that were agreed by a committee
chaired by one of us (GLC) and included the groups that cloned the ionotropic
subunits. In every case, the protein names differ from the corresponding gene
names by two letters (“lu” replaces “RI” – e.g., GRIA1 encodes GluA1 etc). See
Collingridge et al., 2009.
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Neuropharmacology 206 (2022) 108922
compounds he made was N-methyl-D-aspartate, after which the NMDA
receptor was named (Watkins, 1962). NMDA is potent and highly se­
lective for the NMDAR and has been used extensively ever since as a tool
to probe the functions of the NMDAR in health and disease.
2.2.2. NMDA - A tool for inducing synaptic plasticity
We (GLC) applied NMDA to hippocampal slices to test the hypothesis
that this receptor is involved in synaptic plasticity and observed several
intriguing effects (Collingridge et al., 1983a). Local dendritic applica­
tion (by iontophoresis) resulted in (i) a transient depression of the pre­
synaptic fibre volley, (ii) a transient reduction in synaptic transmission
and (iii) a rebound potentiation of synaptic transmission. We suspected
that the depression in the fibre volley was due to presynaptic NMDARs
but couldn’t exclude the possibility that strong postsynaptic depolari­
zation had led to the effect (due to K+ release from the excited neurons).
More recent studies have confirmed the presence of presynaptic
NMDARs on these and other excitatory terminals (e.g., McGuinness
et al., 2010) We assumed that the transient depression of the synaptic
response was due to depolarization leading to a reduced driving force
and shunting of the synaptic potential. Subsequent work suggested that
postsynaptic adenosine release may also be contributing to the effect
(Manzoni et al., 1994a,b).
Regarding the rebound potentiation, we speculated that this is a form
of chemically induced long-term potentiation (LTP) and this prompted
us to examine the effects of NMDAR antagonists on the induction of LTP
(see below). A subsequent more detailed analysis of NMDA-induced
synaptic potentiation, concluded that synaptic stimulation was
required to convert a transient potentiation to a long-lasting potentia­
tion but was unable to identify the missing factor (Kauer et al., 1988). In
another study, NMDA sometimes induced a relatively sustained poten­
tiation with the likelihood of success being increased by co-treatment
with glycine or spermine (Thibault et al., 1989). In yet another study
it was concluded that NMDA triggered two distinct forms of plasticity,
only one of which shared mechanisms with LTP (Asztely et al., 1991).
NMDA-induced potentiation was then used to explore the locus of
change that underlies LTP (Manabe et al., 1992), though the above
observations mean that these findings need to be interpreted with
caution. More recently we re-examined the phenomenon of
NMDA-induced potentiation and concluded that the effects we observed
were unlikely to involve the same processes as LTP of synaptic trans­
mission (Volianskis et al., 2015).
Whether the transient potentiation shares any mechanisms with LTP
or not, the dominant effect of stimulating NMDARs with an agonist, such
as NMDA, is a long-lasting depression of synaptic transmission, partic­
ularly when NMDA is bath-applied (Collingridge et al., 1983a,b). Today,
transient application of NMDA is commonly used to induce LTD on the
assumption that this is engaging the synaptic LTD process. The use of
NMDA to induce LTD is very appealing, since it provides a way of
inducing plasticity at many synapses to enable, for example, biochem­
ical analyses of synaptic plasticity. However, although there are clearly
common mechanisms involved (Lee et al., 1998), there is also evidence
that NMDA application doesn’t engage the protein phosphatase cascade
in the same way as synaptic stimulation (Kameyama et al., 1998).
Indeed, it’s reasonable to assume that exogenous NMDA will activate
receptors that trigger LTP cascades, receptors that trigger LTD cascades
and potentially other plasticity-independent signaling elicited by
neuronal depolarization. Therefore, the use of NMDA to induce LTD
needs to be interpreted with some caution. Despite this, the application
of NMDA has become an extensively studied tool for investigating syn­
aptic plasticity and has led to numerous insights into the underlying
mechanisms.
NMDA has also been used to trigger metaplasticity, the plasticity of
synaptic plasticity (see 2.2.4.4). Metaplasticity is a very important
concept (Abraham and Bear, 1996) that describes how the ability of
synapses to undergo synaptic plasticity can be conditioned by prior
activity at those same synapses (homosynaptic metaplasticity) or other
G.L. Collingridge and W.C. Abraham
synapses on the postsynaptic neurons (heterosynaptic metaplasticity).
Such metaplasticity can be induced using either synaptic activity or
pharmacological agents, amongst other methods. In the case of NMDA,
we (WCA) have shown that a priming delivery of NMDA that failed to
induce LTD by itself caused a metaplasticity effect such that a subse­
quent identical delivery of NMDA did so (Mockett et al., 2007).
2.2.3. Competitive NMDAR antagonists - discovery
Highly selective, competitive NMDAR antagonists were developed in
parallel by the McLennan and Watkins laboratories. Notably, Hugh
McLennan described DL-⍺-amino-adipate as a selective NMDA receptor
antagonist (Hall et al., 1977) and Watkins separate the enantiomers and
demonstrated that the activity resides within the D (R) isomer (Biscoe
et al., 1977). These two laboratories utilised these compounds to provide
the first direct evidence that NMDA receptors mediate synaptic excita­
tion in the CNS (Biscoe et al., 1977). Watkins then went on to describe
other structurally related competitive NMDA receptor antagonists, most
notably the compound referred to as D-2-amino-5-phosphonovalerate
(D-APV2) or D-2-amino-5-phophonopentanoate (D-AP52) (Davies et al.,
1981). (Note: its IUPAC name is (R)-2-Amino-5-phosphonopentanoic
acid. The IUPAC names of the Watkins compounds described in this
article are presented, along with their structures, in Fig. 1. In the text we
stick to the commonly used names). Another important pharmacological
tool from this series is D-CPP (Davies et al., 1986).
2.2.4. Competitive NMDAR antagonists - impacting the field of synaptic
plasticity
2.2.4.1. Long-term potentiation. In 1981, Jeff Watkins generously pro­
vided a sample of his newly synthesized AP5. We (GLC) used this to test
the hypothesis that NMDARs may be the trigger for LTP (Collingridge
et al., 1982, 1983a). We found that AP5 had no detectable effect on basal
synaptic transmission (which we now know is mediated via AMPARs;
see above) but prevented the induction of LTP, in a reversible manner.
Pre-established LTP did not appear to be affected by AP5. These ex­
periments were the first to suggest that NMDARs may play a unique role
in synaptic plasticity, and thus the first to describe a “silver bullet” for
LTP, one that blocked it without affecting basal synaptic transmission.
However, at the time, AP5 was in limited supply and many questions
were left unanswered. The following 40 years has witnessed numerous
studies from hundreds of different laboratories where AP5 (nowadays
the D-isomer) has been used to inhibit synaptic plasticity and these
studies have uncovered many fascinating features regarding the roles of
NMDARs in synaptic plasticity. Some early examples include the
following:
(i). The Cotman laboratory compared a series of phosphonates of
varying carbon chain length (C4–C8) and found that the two
which possessed NMDAR activity (AP5 and AP7)3 inhibited the
induction of LTP whereas the three that were inactive at NMDARs
(AP4, AP6 and AP8) had no effect on LTP (Harris et al., 1984).
They also used AP5 to identify the first example of
NMDAR-independent LTP in the CNS (Harris and Cotman, 1986),
i.e. the mossy fibre pathway that provides a monosynaptic
connection between dentate granule cells and CA3 neurons.
2
Footnote: Jeff Watkins originally named this compound APV where the “V”
refers to “valerate”, the old chemical name. In a subsequent paper, where he varied
the carbon chain length of a series of analogues, he referred to the compound as AP5
(for five carbons). In this review we use the abbreviation of AP5, Watkins preferred
terminology.
3
Footnote. To service the demand for his glutamate receptor ligands, Jeff Watkins
formed a company, Tocris. This enabled the synthesis of his compounds to be scaled
up and for the agents to be rapidly distributed worldwide.
3
Neuropharmacology 206 (2022) 108922
(ii). The Bliss laboratory showed that AP5 inhibited the induction of
LTP in the dentate gyrus in vivo and prevented the associated
increase in L-glutamate release (Errington et al., 1987).
(iii). The Matthies laboratory, that had recently discovered that spaced
tetanisation induced a protein synthesis-dependent form of LTP
(Frey et al., 1988), showed that AP5 and AP7 prevented the in­
duction of this type of sustained LTP (Reymann et al., 1989).
It is now established that there are several forms of AP5-sensitive LTP
that are defined on the basis of their sensitivity to kinase inhibitors
(LTP1 or early (E) LTP), protein synthesis inhibitors (LTP2 or late (L)
LTP) and transcriptional inhibitors (LTP3) (see Bliss and Collingridge,
1993).
(iv) We (GLC) pharmacologically isolated the NMDAR-mediated
synaptic current at CA3-CA1 synapses, defined by its sensitivity
to AP5, and showed that it could support LTP (Bashir et al.,
1991). A similar observation was made independently (Berretta
et al., 1991) though this is not invariably the case (e.g., Muller
et al., 1989). These differences can probably be explained by
multiple forms of LTP (see Bliss and Collingridge, 2013). The
positive findings show that the trigger for synaptic plasticity is
itself plastic.
2.2.4.2. Short-term potentiation. LTP is usually not observed as a step
change in synaptic strength, rather the response peaks shortly after the
induction trigger and then decays to a steady level via a process
generally known as short-term potentiation (STP). Unlike LTP, STP de­
cays in an activity-dependent manner, such that the potentiation persists
until stimulation is applied and then decays at a rate dependent on the
stimulation (Volianskis and Jensen, 2003). Using AP5, we discovered
two kinetically distinct forms of STP. One, which we termed STP1, has
high sensitivity of AP5 (similar to that of LTP) and fast decay kinetics.
The other (STP2) has comparatively low sensitivity to AP5 and slower
decay kinetics (Volianskis et al., 2013). As described elsewhere, we
consider that STP1 and STP2 are triggered by different NMDAR subtypes
with different synaptic locations (see Eapen et al., 2021).
2.2.4.3. Long-term depression and depotentiation. It was already known
that different patterns of synaptic activation could induce long-term
depression (LTD), although at this point little was known about the
significance or mechanisms of LTD. This all changed when several
groups tested the sensitivity of various forms of LTD to AP5. In partic­
ular, AP5 was found to prevent the induction of depotentiation (Fujii
et al., 1991) and the induction of de novo LTD in slices prepared from
young animals (Dudek and Bear, 1992). These two forms of LTD are
homosynaptic. We (WCA) showed that heterosynaptic LTD is also sen­
sitive to AP5 (Christie and Abraham, 1992a). These discoveries, all
based on AP5, extended the range of types of synaptic plasticity that are
triggered by the synaptic activation of NMDARs (see Collingridge et al.,
2010).
2.2.2.4. Metaplasticity. The availability of these selective NMDAR an­
tagonists also played a pivotal role in the discovery of metaplasticity
phenomena, a term coined by one of us (WCA) to describe a family of
effects whereby the prior history of synaptic or cellular activity regulates
the induction, valence or persistence of subsequently induced synaptic
plasticity (or at a behavioural level, memory storage) (Abraham and
Bear, 1996). For example, we found that priming stimulation given to
lateral perforant path fibres in vivo primed them for subsequent induc­
tion of LTD in the dentate gyrus by interleaved dual theta-pattern
stimulation of both the medial and lateral path inputs. This effect was
blocked by CPP when given prior to priming, but not after, revealing the
NMDAR-dependence of the priming effect (Christie and Abraham,
1992b). The priming of LTD induction by NMDAR activation even
G.L. Collingridge and W.C. Abraham
Fig. 1. Some of the glutamate receptor ligands developed by Jeff Watkins.
NMDA: N-Methyl-D-aspartic acid; DαAA: (R)-2-Aminohexanedioic acid; DAP5: (R)-2-Amino-5-phosphonopentanoic acid; (R)-CPP: (R)-4-(3-Phosphonopropyl)
piperazine-2-carboxylic acid; γ-DGG: γ-D-Glutamylglycine; ACPD: (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid; LAP4: (S)-2-Amino-4-phosphonobutanoic
acid; (S)-MCPG: (S)-4-(1-Amino-1-carboxyethyl)benzoic acid.
occurs during normal homosynaptic LTD protocols, which typically
entail a long train of low-frequency pulses. Thus, the pulses early in the
train don’t produce much LTD themselves, but rather prime in an
AP5-sensitive manner the synapses for the bulk of LTD induction that
occurs later in the train (Mockett et al., 2002). This finding was
consistent with the above-mentioned priming of LTD by NMDA treat­
ment. Conversely, priming stimulation was also found to impair the
induction of subsequent LTP, an effect that was AP5-sensitive and thus
also NMDAR-dependent (Huang et al., 1992). This finding built upon
our (GLC) earlier report that low-frequency activation of NMDARs under
low Mg2+ conditions (see below) can inhibit future LTP, an effect also
blocked by AP5 (Coan et al., 1989). Thus these antagonists proved
instrumental in revealing a further role for NMDARs beyond the in­
duction of LTP and LTD, i.e., the metaplastic biasing of future plasticity
towards LTD and away from LTP.
2.2.4.5. Learning and memory. It was generally assumed that synaptic
plasticity was a critical component of learning and memory. The
development of AP5 enabled this association to be tested directly.
Richard Morris and colleagues showed that a concentration of AP5 that
prevented the induction of LTP in vivo was able to impair spatial learning
and memory, using the watermaze that he developed (Morris et al.,
1986). Since this pioneering experiment, AP5 and other competitive
NMDAR antagonists have been used extensively to investigate the roles
of NMDARs in various forms of learning and memory.
D-AP5 has limitations for in vivo work since it needs to be infused
directly into the brain. Jeff Watkins designed analogues that could more
readily pass the blood-brain-barrier, such as D-CPP (Davies et al., 1986).
Shortly after, we (WCA) demonstrated that peripheral injection of the
mixed isomer of CPP could indeed be used to block LTP in the dentate
gyrus in vivo, as well as heterosynaptic LTD (Abraham and Mason,
1988). This work validated CPP as a tool, along with other agents such as
MK-801, that can be administered peripherally to understand the effects
of blocking NMDARs in behaving animals in order to identify molecular
correlates of LTP such as CREB phosphorylation (Abraham et al., 2002)
and immediate early gene expression (Demmer et al., 1993), avoiding
the need for invasive brain cannulation procedures. In parallel, we used
CPP to assess the contribution of NMDARs to performance on a variety of
learning tasks (Tan et al., 1989; Ward et al., 1990).
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Neuropharmacology 206 (2022) 108922
2.2.5.1. Magnesium - the discovery of its ability to selectively block
NMDARs. While studying the excitation of spinal cord neurons by a
range of glutamate receptor analogues, Evans and Watkins made the
totally unexpected discovery that magnesium ions (Mg2+) are a highly
selective inhibitor of the NMDA receptor (Ault et al., 1980; Evans et al.,
1977). They showed that Mg2+ was effective in the low micromolar
range and that at physiological Mg2+ concentrations (~1 mM) NMDA
responses were substantially antagonized (>90%). They further showed
that Mg2+ acts non-competitively and assumed it might be blocking the
ion channel.
2.2.5.2. Magnesium - understanding the operation of Hebbian synapses.
Prompted by the study of Evans and Watkins, we examined the effects of
removing Mg2+ from the perfusate on synaptic transmission in the
hippocampus (Coan and Collingridge, 1984, 1985). We (GLC) observed
a massive increase in synaptic excitability, most of which was reversed
by D-AP5. This demonstrated that NMDARs can be readily activated by
low-frequency stimulation but are largely prevented from doing so by
the Mg2+ present in the perfusate. Around this time, two seminal studies
showed that the ability of Mg2+ to inhibit NMDARs was highly
voltage-dependent (Nowak et al., 1984; Mayer et al., 1984) and due to a
rapid block of the ion channel. We immediately realized that the
voltage-dependence of the Mg2+ block has physiological relevance in
the context of the induction of LTP (Collingridge, 1985). We proposed
that during high-frequency transmission the temporal summation of
AMPAR-mediated EPSPs provided the necessary depolarization to
temporally relieve the Mg2+ block of NMDARs sufficiently to trigger
LTP. Consistent with this model, we observed a slowly developing syn­
aptic component during high-frequency stimulation that was eliminated
by D-AP5 (Herron et al., 1986; Collingridge et al., 1988b). The strong
depolarisations generated by the NMDAR-EPSP also drives complex
spiking behaviour of CA1 pyramidal cells in vivo (Abraham and Kairiss,
1988).
By now, many groups had become interested in the role of NMDARs
in LTP and the realization emerged that this mechanism could explain
key physiological properties of LTP, including input specificity, coop­
erativity, and associativity (see Bliss and Collingridge, 1993). Hebb had
famously postulated that synapses become stronger when pre- and
postsynaptic neurons fire at roughly the same time. The
voltage-dependent Mg2+ block provides a molecular explanation for this
G.L. Collingridge and W.C. Abraham
coincidence detection — presynaptic activity is necessary to release
L-glutamate and postsynaptic activity (which may or may not involve
action potential firing) alleviates the Mg2+ block. In a powerful
demonstration of this effect, several groups showed how simply depo­
larizing neurons facilitated the induction of LTP via the activation of
NMDARs. In particular, we (WCA) showed, using sharp electrode
intracellular recordings, that pairing strongly depolarizing postsynaptic
current pulses with very low-frequency afferent stimulation generated
an AP5-sensitive LTP (e.g., Wigström et al., 1986; Gustafsson et al.,
1987). As for LTP induced by high-frequency stimulation, this
pairing-induced LTP was input-specific, consistent with the need for
coincident synaptic activity and depolarization to open NMDAR chan­
nels. Interestingly, the depolarization was still effective when delivered
50–100 ms after the synaptic stimulation, which is consistent with the
slow nature of the NMDAR-mediated synaptic response (Collingridge
et al., 1988a; see below). This pairing protocol foreshadowed the
development of spike-timing-dependent plasticity protocols in common
use today for inducing AP5-sensitive LTP and LTD in many brain regions
(Markram et al., 1997; Bi and Poo, 1998).
Prior to 1984 it was thought, from studies in the spinal cord, that
NMDARs mediate a polysynaptic response and that this explains its slow
nature compared to the AMPAR mediated response. However other
Bristol researchers showed, using D-AP5 provided by Watkins, that in
Xenopus embryos NMDARs could mediate a slow monosynaptic EPSP
(Dale and Roberts, 1985). We immediately realized that a similar situ­
ation likely applied to the hippocampus and our hypothetical models
were based on such a notion. This idea of a monosynaptic
NMDAR-mediated EPSP in the hippocampus met with considerable
skepticism at the time. We therefore set out to investigate whether
indeed NMDARs mediate a monosynaptic EPSP at CA3-CA1 synapses
and, if so, to determine the underlying kinetics. To achieve this we
depolarized neurons out of the range of the Mg2+ block, then
voltage-clamped the neuron and used D-AP5 to determine the
NMDAR-mediated component. This isolated an AMPAR mediated syn­
aptic current and, by subtraction, a NMDAR-mediated synaptic current.
We found that the NMDAR component has a much slower rising phase
and was much longer lasting than the AMPAR component. (Collingridge
et al., 1987, 1988). Around this time another group also reported the
slow nature of the NMDAR-mediated EPSP, defined using D-AP5, at
synapses between cultured hippocampal or spinal cord neurons (For­
sythe and Westbrook, 1988). In their study, they were concerned that
the slow rise of the NMDAR-EPSC was a space-clamp artifact. However
we believed the slow rise in our experiments to be an accurate repre­
sentation of the synaptic conductance since, despite the extensive den­
dritic arborization of hippocampal CA1 pyramidal neurons, we could
isolate the faster-rising NMDAR-insensitive (i.e. AMPAR-mediated)
synaptic component. Indeed, the PhD student in our team (Robin Les­
ter) moved to Craig Jahr’s lab where he used D-AP5 to demonstrate how
the kinetics of NMDAR channels fully explain the slow time-course of the
NMDAR-mediated synaptic response (Lester et al., 1990). Shortly after
our initial studies were complete, the quinoxalinedione AMPAR antag­
onists were described (see above) and we and others were able to
measure the NMDAR-mediated synaptic current and its
voltage-dependent Mg2+ block directly, over a wide range of membrane
voltages (e.g., Alford et al., 1993). It is now firmly established that the
slow kinetics of the NMDAR-mediated synaptic response is fundamental
to its role as a coincidence detector.
Another key factor that regulates NMDAR function is the level of
GABA-mediated synaptic inhibition. We (Herron et al., 1985; Colling­
ridge et al., 1988a) and others (e.g., Dingledine et al., 1986) blocked
synaptic inhibition and showed using D-AP5 that single shock stimula­
tion was able to activate NMDARs. Significantly, with sufficiently strong
synaptic activation, this procedure could alone generate LTP without
tetanisation (Abraham et al., 1987). These pharmacological experiments
showed how important the hyperpolarising effect of GABA is, with
respect to limiting the Mg2+ block of the NMDAR conductance. (Up until
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Neuropharmacology 206 (2022) 108922
this point the shunting action of GABA had been considered to be the
more important function of this inhibitory neurotransmitter). Around
this time it was shown that LTP could be very efficiently induced by
patterns of synaptic activity delivered at the theta frequency, a fre­
quency associated with exploratory behaviour. By the use of D-AP5 it
was shown that the theta frequency was especially effective at sup­
pressing synaptic inhibition to enable the synaptic activation of
NMDARs (Larson and Lynch, 1988; Diamond et al., 1988). We then went
on to show that this suppression of GABA-mediated synaptic inhibition
was due to a GABA-B autoreceptor mechanism and that the optimal
timing (i.e., theta) was determined by the kinetics of the presynaptic
GABA-B receptor-mediated action (Davies et al., 1990, 1991). Collec­
tively, these D-AP5 studies demonstrated the critical physiological role
of GABA in regulating the synaptic activation of NMDARs, via influ­
encing the extent of Mg2+ block.
It was assumed that, when activated synaptically, NMDARs would
locally increase Ca2+ and that this would serve as the trigger for the
persistent changes in synaptic strength. This idea gained support with
the observation that NMDARs directly flux Ca2+ (MacDermott et al.,
1986). We therefore embarked on a series of experiments to investigate
whether this synaptic NMDAR-induced Ca2+ signal could be detected at
synapses (Alford et al., 1993). In voltage-clamped neurons we evoked a
synaptic current during high-frequency stimulation that comprised
AMPAR and NMDAR-mediated components and recorded the associated
Ca2+ signals in small regions of dendrites and in individual dendritic
spines using a fluorescent Ca2+ indicator. Blocking AMPARs had no ef­
fect on the Ca2+ signal whereas blocking NMDARs with AP5 eliminated
the Ca2+ signal. Since this was the first time that a synaptic Ca2+ signal
had been observed directly we were interested in understanding its
properties. The signal was highly localized (presumably to activated
synapses), transient and involved a substantial component triggered by
Ca2+ release from intracellular stores. The ability to detect Ca2+ in
dendritic spines through NMDAR-triggered release of Ca2+ from stores
was then elegantly exploited by the Bliss laboratory by undertaking an
optical quantal analysis of LTP. They confirmed the NMDAR dependence
of their signals, using AP5 (Emptage et al., 1999), and went on to
perform the most definitive quantal analysis of LTP to date (Emptage
et al., 2003; Ward et al., 2006).
2.3. Kainate receptors
2.3.1. Kainate receptors - discovery
The early pharmacological experiments from the groups of Watkins
and McLennan were suggestive of the existence of two distinct types of
non-NMDA ionotropic receptors. However, the most definitive evidence
that kainate receptors (KARs) and AMPARs are distinct entities was the
observation made by Dick Evans that kainate depolarized primary
afferent fibres, whereas compounds acting at AMPARs, such as quis­
qualate, were largely inactive (Agrawal and Evans, 1986). Since these
early experiments, it has been established that kainate receptors are a
family of tetramer receptors, for which five potential subunits exists
(GluK1-5). Unfortunately, the prototypic agonist, kainate, acts on both
AMPARs and KARs. However, the development of selective kainate re­
ceptor antagonists has enabled the separate roles of KARs and AMPARs
to be determined.
2.3.2. Kainate receptors – roles in synaptic plasticity
Although Watkin’s DGG was an effective KAR antagonist, it was of
low potency and lacked selectivity. The elucidation of the roles of kai­
nate receptors in the regulation of synaptic transmission and in synaptic
plasticity followed the development of more potent and selective kainate
receptor antagonists. This occurred in parallel at Eli Lilly by a team led
by David Lodge and David Bleakman, with compounds such as
LY382885 (Bortolotto et al., 1999) and in the former Watkin’s labora­
tory in Bristol under the leadership of David Jane, with compounds such
as ACET (Dargan et al., 2009). These two groups also identified more
G.L. Collingridge and W.C. Abraham
selective kainate receptor agonists. In particular, Evans and Watkins
identified the potent excitatory action of willardiine (1-(2-amino-2-­
carboxyethyl)pyrimidine-2.4-dione) (Evans et al., 1980) and went on to
present evidence that 5-bromowillardiine may be a selective kainate
receptor agonist (Agrawal and Evans, 1986).
These pharmacological studies were complemented by the genera­
tion of the knockouts of the five genes in the laboratory of Stephen
Heinemann. The role of KARs in synaptic plasticity is complex and, in
some places, controversial. Suffice to say, we found that mossy fibre
LTP, defined by its insensitivity to AP5, was prevented by kainate re­
ceptor antagonists (Bortolotto et al., 1999). A review of this field is
beyond the scope of the present article but has been discussed in depth
elsewhere (Jane et al., 2009).
2.4. Metabotropic glutamate receptors
2.4.1. Metabotropic glutamate receptors – discovery
Prior to the realization that L-glutamate could activate a family of G-
protein coupled, metabotropic glutamate receptors (mGluRs), Watkins
had already separated and studied the actions of the enantiomers of AP4
and AP3 on synaptic transmission in the spinal cord. L-AP4 was found to
be a potent inhibitor of synaptic transmission. Jeff Watkins also supplied
L-AP4 to the Cotman laboratory which used it to demonstrate the potent
activity of this agent on synaptic transmission at the lateral perforant
pathway projection from the entorhinal cortex to the dentate gyrus
(Koerner and Cotman, 1981). At the time, these effects were assumed to
be due to antagonist actions at ionotropic glutamate receptors.
With the demonstration that glutamate could stimulate the forma­
tion of inositol trisphosphate production (Sladeczek et al., 1985; Nic­
oletti et al., 1986; Sugiyama et al., 1987), it was clear that L-glutamate,
like other neurotransmitters such as acetylcholine, could also activate
G-protein coupled receptors. The laboratory of Nakanishi then cloned
the first (Masu et al., 1991) of what is now known to be a family of eight
(mGlu1-mGlu8) mGluR members. Since these pioneering studies, there
has been huge progress in the understanding of the function of mGluRs
in health and disease (see Nicoletti et al., 2011).
To advance the understanding of the roles of mGluRs in neuronal
function, selective ligands were urgently required. Early, important
compounds were the agonist “trans-ACPD” (Palmer et al., 1989) and the
antagonist DL-AP3 (Schoepp and Johnson, 1989). In collaboration with
Jeff Watkins, we showed that the agonist activity resided in the 1S,
3R-isomer of ACPD (technically a cis isomer) and the antagonist activ­
ity resided in the L-enantiomer of AP3 (Irving et al., 1990). 1S,3R-ACPD
and L-AP3 have since been used extensively as experimental tools to
probe the functions of mGluRs.
A major breakthrough came with the development of the phenyl­
glycine antagonists by Jeff Watkins (Jane et al., 1993). In collaboration
with Jeff Watkins, we tested a range of phenylglycine antagonists on
synaptic function in the hippocampus, in a blinded manner, and
observed optimal activity with MCPG. We went on to show that MCPG
was effective at cloned mGlu1 receptors in expression systems and that it
antagonized the actions of 1S,3R-ACPD on native receptors in hippo­
campal neurons (Bashir et al., 1993). MCPG has since been shown to
inhibit several (mGlu1, mGlu2, mGlu3, mGlu5, mGlu8), but not all,
mGluR members and has been used extensively to investigate the
functions of mGluRs in health and disease. Other phenylglycine antag­
onists that were developed by Watkins around this time included 4-CPG,
MAP4 and MCCG (reviewed in Watkins and Collingridge, 1994). The
emerging potential therapeutic interest in mGluRs then drove the
development of a variety of more potent and subtype specific mGluR
antagonists, which in turn has helped identify roles of mGluRs in
numerous neuronal functions, including several types of synaptic plas­
ticity (see, Nicoletti et al., 2011).
6
Neuropharmacology 206 (2022) 108922
2.4.2. Metabotropic glutamate receptors – roles in synaptic plasticity
2.4.2.1. Long-term potentiation. The first suggestion that mGluRs may
be involved in synaptic plasticity was the finding that L-AP3 inhibited
the induction of LTP at CA3-CA1 synapses (Behnisch et al., 1991). We
then identified MCPG as the most effective of Jeff Watkins’ initial series
of phenylglycine antagonists at preventing slow-onset potentiation
induced by (1S,3R)-ACPD (Bortolotto & Collingridge, unpublished). We
therefore used MCPG to further investigate the function of mGluRs in
hippocampal synaptic plasticity at CA3-CA1 synapses. In our hands,
MCPG completely eliminated LTP induced by a single tetanus whereas
L-AP3 was ineffective (Bashir et al., 1993). This effect was specific in
that baseline synaptic transmission, pre-established LTP and STP were
all unaffected and the block of LTP induction was fully reversible upon
washout of MCPG and delivery of a second tetanus. These observations
suggest that MCPG-sensitive mGluRs act as co-triggers with NMDARs in
the induction of LTP. MCPG was also found to inhibit the induction of
LTP at the perforant path synapse in vivo (Riedel and Reymann, 1993;
Richter-Levin et al., 1994).
We also found that MCPG inhibited the induction of AP5-insensitive,
mossy fibre LTP (Bashir et al., 1993), suggesting that mGluRs can also
function as co-triggers with kainate receptors in the induction of LTP. In
these slice studies we found that either MCPG or kainate receptor an­
tagonists completely prevented the induction of AP5-insensitive LTP
(Bashir et al., 1993; Bortolotto et al., 1999). However, in anaesthetised
rats we found that a combination of MCPG plus kainate receptor an­
tagonists was required to inhibit the induction of LTP (Wallis et al.,
2015). This difference may relate to the underlying excitability of tissue
in vitro vs in vivo.
2.4.2.2. Short-term potentiation. A clear distinction between NMDAR
and mGluR antagonists is that the former, but not the latter, generally
inhibit the induction of STP. The early studies using MCPG observed
considerable variability in the time-course of the initial MCPG-resistant
potentiation. This can now be explained, at least in part, on the activity-
dependence of the decay of STP (see 2.2.4.2). In those studies using a
relatively fast rate of basal stimulation, the MCPG-insensitive compo­
nent was fairly short-lived (Bashir et al., 1993) whereas when basal
stimulation was intermittent this component persisted for longer (Riedel
and Reymann, 1993). Other differences between in vitro and in vivo
recording conditions may also have been a contributing factor.
2.4.2.3. Long-term depression and depotentiation. MCPG was the tool
that was first used to identify a role of mGluRs in LTD. We found that
MCPG was able to completely prevent depotentiation of LTP at CA1
synapses (Bashir and Collingridge, 1994; Bortolotto et al., 1994). It was
then shown that MCPG could prevent the induction of de novo LTD in
slices obtained from very young animals (Bolshakov and Siegelbaum,
1994). MCPG, and subsequently other mGluR antagonists, have since
been used to identify roles of mGluRs in LTD at many other pathways in
the CNS. It should be noted that D-AP5, and other NMDAR antagonists,
have also been shown to inhibit depotentiation and de novo LTD (see
2.2.4.3). What determines the relative roles of NMDARs vs mGluRs in
these forms of LTD has not been firmly established. However, it is worth
adding that some, but not all, forms of NMDAR-LTD involve a metabo­
tropic action, since they are blocked by competitive antagonists, such as
D-AP5, but not are unaffected by non-competitive antagonists, such as
those that target the glycine site (Nabavi et al., 2013). The notion is that
agonist binding in the absence of channel activity triggers a metabo­
tropic function of NMDARs. However, it is also possible that these
metabotropic effects involve an interaction between NMDARs and the
canonical mGluRs.
2.4.2.4. Metaplasticity. The observation that MCPG inhibited LTP was
controversial with some groups reporting no effect of MCPG on the
G.L. Collingridge and W.C. Abraham
induction of LTP (e.g., Manzoni et al., 1994b; Selig et al., 1995). Indeed,
the field was roughly evenly split between laboratories reporting an
effect of MCPG or not. The obvious conclusion was that MCPG-sensitive
receptors were involved in, but not essential for, LTP at hippocampal
synapses and led to the question as to what factors determined their
requirement. One possibility, left open by the critics (Selig et al., 1995),
was that MCPG-sensitive receptors may modify the threshold for the
induction of LTP. Consistent with this idea, MCPG was found to inhibit
the induction of LTP induced by a weak but not strong induction pro­
tocol under otherwise identical conditions (Wilsch et al., 1998). It was
proposed that with a weak induction stimulus activation of mGluRs was
required to release Ca2+ from intracellular stores whereas with a strong
induction stimulus this was bypassed by Ca2+ entry via voltage-gated
Ca2+ channels. However, the strength of induction is not the only fac­
tor in play.
Prompted by the emerging controversy, we (GLC) further investi­
gated the ability of MCPG to inhibit the induction of LTP at CA3-CA1
synapses. We found that its ability to inhibit LTP depended upon the
prior history of mGluR activation, via a process we named the “molec­
ular switch” (Bortolotto et al., 1994), which is a form of what was later
termed metaplasticity (Abraham and Bear, 1996). We found that if we
induced LTP, reduced the stimulation intensity to match the original
baseline and then delivered a second tetanus to the same pathway, we
could induce additional LTP that was completely resistant to MCPG. By
using a two-input protocol we demonstrated MCPG-sensitive and
MCPG-insensitive LTP at the same neuronal population. This not only
provided a convincing demonstration of two types of LTP (MCPG-sen­
sitive and MCPG-insensitive) but also that the metaplastic effect was
confined to the stimulated input – that is to say a form of homosynaptic
metaplasticity. The ability of synaptic activation to trigger this form of
metaplasticity was dependent on activation of MCPG-sensitive mGluRs
and was independent of the synaptic activation of NMDARs. It could also
be triggered by the pharmacological activation of mGluRs using, for
example, the agonist 1S,3R-ACPD (Bortolotto et al., 1994).
In subsequent work, we went on to demonstrate that the induction of
metaplasticity was due to activation of mGlu5 receptors, since it was
completely prevented by MPEP. Indeed, activation of mGlu5 receptors
may be sufficient to trigger the metaplasticity since the transient
application of the mGlu5 selective agonist (RS)-2-chloro-5-hydrox­
yphenylglycine (CHPG) (Doherty et al., 1997) led to subsequent LTP
being resistant to MCPG (Bortolotto et al., 2005). This conclusion was
supported by a comparison of the effects of MCPG in three KO mouse
models: mGlu1− /− , mGlu5− /− , and mGlu7− /− . The metaplastic effect
was eliminated in the Glu5 KO but readily induced in both the mGlu1
and mGlu7 KOs (Bortolotto et al., 2005). In terms of downstream
signaling molecules, the metaplasticity effect requires activation of
CaMKII and conventional PKC isoforms but not PKA (Bortolotto and
Collingridge, 1998, 2000). It is interesting to note that the triggering of
metaplasticity is highly sensitive to inhibition of CaMKII (more so than
the induction of LTP per se) and that it requires very few stimuli
(threshold number ~5 stimuli; threshold frequency ~ 3Hz) for its acti­
vation (Bortolotto et al., 2008). It seems likely, therefore, that this form
of metaplasticity is frequently encountered in situ.
In a corresponding parallel set of experiments, we (WCA) found that
a brief application of (1S,3R)-ACPD was able to prime later LTP, such
that a mild tetanus protocol that normally induced a decaying form of
LTP resulted in a substantially enhanced and more persistent LTP
(Cohen and Abraham, 1996). This effect was blocked by AP3, but was
independent of NMDAR activation as AP5 administration during ACPD
delivery did not block the effect. It was also not due to a lasting
potentiation of isolated NMDAR-mediated responses. However, the ef­
fect was associated with an increased cell excitability and depression of
the slow afterhypolarization (sAHPs) that persisted long after ACPD
washout, with the reduction in the subsequent TBS-generated sAHPs
being highly correlated with the degree of LTP induced (Cohen et al.,
1999). This metaplastic priming effect was also elicited by DHPG,
7
Neuropharmacology 206 (2022) 108922
blocked by MCPG, and dependent on the activation of phospholipase C,
all consistent with the effect being mediated by group I mGluRs (Cohen
et al., 1998). A key discovery was that this priming enhancement of LTP
persistence was prevented if the priming stimulus was delivered in the
presence of inhibitors of de novo protein synthesis (Raymond et al.,
2000). And as for the molecular switch effect described above, this
priming effect was input specific, and could also be generated by syn­
aptic priming stimulation in the presence of AP5. Moreover, once the
DHPG priming stimulus had been delivered, the subsequently induced
LTP was not affected by a protein synthesis inhibitor given during the
LTP induction protocol. This means that group 1 mGluR activation plays
a critical role in generating this component of LTP via stimulation of the
translational machinery, even if that is done at a different time to when
the NMDAR activation occurs to trigger LTP induction (Raymond et al.,
2000).
Other metaplastic effects involving mGluRs have also been reported.
For example, the Reymann and Nicoletti labs found that LTP was asso­
ciated with a delayed increase in the ability of mGluRs to trigger
phosphoinositide hydrolysis, using either ACPD or ibotenic acid as
mGluR agonists (Aronica et al., 1991). Since mGluRs regulate intracel­
lular biochemistry it is likely that metaplastic effects are a common
occurrence.
But what is the identity of the MCPG-sensitive receptor that is
responsible for the induction of LTP when there has not been a metaplastic
trigger? The pharmacology of this receptor does not readily match that of
the eight conventional subtypes (Bortolotto and Collingridge, 1998).
Furthermore, LTP can be readily induced at these synapses in the mGlu1
KO, the mGlu5 KO and in the mGlu1/5 double KO (Bortolotto et al.,
2005). This led us to assume that the MCPG-sensitive receptor may be a
novel metabotropic receptor. However, the ability of MCPG to inhibit the
induction of LTP depends on the strength of tetanisation, with strong in­
duction protocols bypassing the need for their activation (Wilsch et al.,
1998). We had also shown that activation of group I mGluRs, by (1S,
3R)-ACPD (Harvey and Collingridge, 1993), DHPG (Fitzjohn et al., 1996)
or CHPG (Doherty et al., 1997), can rapidly and greatly enhance the
activation of NMDARs. This acute effect of mGluR activation is sensitive to
MCPG (Fitzjohn et al., 1996). Therefore, another possibility is that acti­
vation of mGlu1 and/or mGlu5 is required when a weak induction pro­
tocol is used to boost the activation of NMDARs. Indeed, pharmacological
inhibition of mGlu1 receptors has been shown to prevent the induction of
LTP at these synapses (Tigaret et al., 2018). The proposed mechanism is
that activation of mGlu1 facilitates induction of LTP by inhibition of SK
channels, which otherwise oppose the synaptic activation of NMDARs.
In conclusion, it appears that mGlu receptors have at least two
distinct roles in the induction of LTP. One is to facilitate the synaptic
activation of NMDARs during LTP induction, a requirement that can be
bypassed by strong activation. This effect may be due to an interaction
between mGluRs and NMDARs and may involve mGlu1 receptors.
Another is to induce a metaplasticity state, via the activation of mGlu5
receptors, to trigger de novo protein synthesis for LTP maintenance. One
effect of this metaplasticity is the bypassing of the need for further
mGluR activation for the generation of additional LTP, as found in the
molecular switch experiments (Bortolotto et al., 1994). Another is to
enhance the magnitude of LTP (Cohen and Abraham, 1996). The authors
of this chapter consider these to be two manifestations of the same form
of metaplasticity, as shown schematically in Fig. 2.
2.4.2.5. Learning and memory. The ability of MCPG to inhibit LTP in
vivo paved the way for understanding the functions of mGluRs in
learning and memory (Riedel and Reymann, 1993; Richter-Levin et al.,
1994). These pioneering studies implicated mGluRs in spatial learning
and memory (Richter-Levin et al., 1994; Riedel et al., 1994). Subse­
quently, considerable information has been obtained regarding the roles
of the various mGluR subtypes in learning and memory (see, Mukherjee
and Manahan-Vaughan, 2013).
G.L. Collingridge and W.C. Abraham Neuropharmacology 206 (2022) 108922

Fig. 2. Metaplasticity triggered by mGluRs. A-C are pooled data plots of fEPSPs (normalized slopes in A,B and % change in C) versus time (in hours). A, shows that
200 μM (S)-MCPG completely prevents the induction of LTP, without affecting STP, in a reversible manner. After following LTP for 1 h the stimulus intensity was
reduced to match the original baseline. MCPG failed to prevent LTP in response to a further tetanus. The blue arrows indicate when each tetanus (100 Hz, 1 s, test
intensity) was delivered. B, shows that a series of tetani delivered in the present of 50 μM AP5 prevented MCPG from inhibiting LTP. C. Shows that a TBS in the
presence of 50 μM AP5 results in a subsequent TBS inducing a larger LTP. The priming effect of the first TBS is completely prevented by the protein synthesis in­
hibitor, emetine (20 μM). D. The authors view the “molecular switch” illustrated in A and B and the “priming” illustrated in C as two manifestations of the same form
of metaplasticity. Upper panel: Under baseline conditions when a relatively weak tetanus in delivered the activation of mGluRs (purple symbol) boosts the synaptic
activation of NMDARs (red symbols) to enable LTP, via the insertion of additional AMPARs (yellow symbols). Consequently, MCPG prevents the induction of LTP.
Middle panel: A strong induction can negate the need for the synaptic activation of mGluRs and hence MCPG is ineffective. This may be due to a stronger postsynaptic
depolarization (depicted by the deeper colour). Lower panel: A priming stimulus (here a high frequency stimulation in the presence of AP5) activates mGlu5 receptors
to trigger de novo protein synthesis. This process involves conventional protein kinase C isoforms (PKC) and calcium and calmodulin-dependent protein kinase
(CaMK) isoforms. The newly synthesized proteins may include additional AMPAR subunits and structural proteins to enable spine growth to accommodate the
additional AMPARs. Corresponding presynaptic changes are likely to occur (not illustrated). Data in A and B replotted from Bortolotto et al. (1994). Data in C
replotted from Raymond et al. (2000).

2.4.2.6. Agonist-induced plasticity. As is the case with NMDAR-mediated
synaptic plasticity, agonists have been employed extensively to study
the mGluR-dependent forms of synaptic plasticity. For example, when
we tested (1S,3R)-ACPD on CA3-CA1 synapses, we observed a robust
slow-onset potentiation (Bortolotto and Collingridge, 1993, 1995). This
effect was stereospecific since the (1R,3S)-enantiomer had no effect.
This form of synaptic plasticity was not blocked by D-AP5 but fully
occluded NMDAR-LTP, suggesting that it was triggering the same form
of LTP that is ordinarily induced via the synaptic activation of NMDARs
but by engaging the mechanisms downstream of NMDAR activation. The
potentiation was, however, prevented by inhibitors of PKC and Ca2+
release from intracellular stores. These observations are consistent with
the activation of a group 1 mGluR engaging classical LTP.
The time-course of the slow-onset potentiation was consistent with
the induction of LTP in the complete absence of STP. We found that this
form of synaptic potentiation required either intact circuitry between
CA3 and CA1 or for a tetanus to be delivered. The latter was effective in
the presence of D-AP5, demonstrating that the high-frequency stimula­
tion was required for effective mGluR engagement. The slow-onset
potentiation was associated with an increase in sensitivity of neurons
to exogenously administered AMPA and in single neurons was prevented
by postsynaptic BAPTA. Therefore it can be concluded that mGluR-
triggered LTP involves a postsynaptic induction and postsynaptic
expression process (although an additional presynaptic component
cannot be excluded). Since it fully cross-saturated with canonical LTP1,
then it can be assumed that LTP1 similarly involves a postsynaptic
change, a view which is consistent with the majority of data for LTP1 at
this synapse (see Bliss and Collingridge, 2013). So why the requirement
for some form of synaptic activity to engage the mGluR mechanism? One
possibility is that the mGlu receptor acts as an additional coincidence
detector, sensing agonist binding and neuronal depolarization; consis­
tent with this notion we observed that the ability of group I mGlu ago­
nists to mobilise Ca2+ from intracellular stores in hippocampal neurons
was greatly enhanced by either modest increases in K+ or by a low dose
(3 μM) of NMDA, both of which loaded the stores with Ca2+ (Rae et al.,
2000). It is important to note, given the specific conditions required to
induce slow-onset potentiation with (1S,3R)-ACPD, that this phenome­
non is also observed in vivo (Manahan-Vaughan and Reymann, 1995).
In addition to triggering a form of LTP, (1S,3R)-ACPD can induce
LTD at CA3-CA1 synapses in immature animals (Overstreet et al., 1997).
This form of LTD was prevented by both MCPG and D-AP5, which might
be attributed to a mGluR facilitation of the canonical NMDAR-LTD that
is prominent in immature hippocampus. In more mature slices, we found
that (1S,3R)-ACPD was unable to induce LTD. In contrast, the group I
mGluR agonist, DHPG generated a robust LTD at CA3-CA1 synapses in
both 4–10 week (Palmer et al., 1997) and 12–18 day old (Fitzjohn et al.,
1999) tissue. In both cases, this effect was mimicked by the mGlu5 se­
lective agonist CHPG. DHPG-LTD has since become a frequently used
component of the synaptic plasticity tool box, including for studies of
LTD of NMDAR-mediated synaptic transmission (Ireland and Abraham,
2009). However, there are some important points to note when using
DHPG to generate synaptic plasticity. Firstly, there are two distinct

8
G.L. Collingridge and W.C. Abraham
forms of DHPG-LTD: one that requires activation of NMDARs and one
which does not (Palmer et al., 1997). Secondly, DHPG induces LTD that
can have characteristics of a presynaptic expression (e.g., Fitzjohn et al.,
2001) or a postsynaptic expression (e.g., Moult et al., 2006) mechanism,
or both (e.g., Mockett et al., 2011). Third, DHPG induces LTD that may
require or may be totally independent of the need for de novo protein
synthesis. Fourth, DHPG-induced LTD does not necessarily occlude with
synaptically induced mGluR-LTD. Fifth, DHPG can induce LTD in the
absence of extracellular Ca2+. Sixth, the LTD induced by an agonist can
be readily reversed long after the agonist has cleared the system. The
LTD is re-established upon washout of the antagonist and probably in­
volves the triggering of a constitutively active state of the receptor by the
agonist. This strange phenomenon was discovered using DHPG and
MCPG (Palmer et al., 1997) but applies to all three groups of mGluRs
(Lodge et al., 2013). Synaptically induced mGluR-LTD does not exhibit
this phenomenon. Considered together, it can be concluded that DHPG
can induce more than one form of LTD and shares only some properties
with synaptically induced mGluR-LTD.
In addition to inducing synaptic plasticity, mGluR agonists can also
trigger intrinsic plasticity, i.e. lasting changes in membrane excitability.
For example, we (GLC) observed that (1S,3R)-ACPD depolarized neu­
rons and inhibited spike frequency adaption via an MCPG-sensitive re­
ceptor with a pharmacology consistent with a group I mGluR (Davies
et al., 1995). We (WCA) observed similar effects with DHPG, and
showed that they were gated by tyrosine phosphatases (Ireland et al.,
2004). Interestingly, both mGluR1 and mGluR5 contributed to this
intrinsic plasticity, since both MPEP and LY367385 were required to
completely block the DHPG effects (Ireland and Abraham, 2002). The
effects of activating mGluRs on neuronal excitability can persist long
after washout of the agonist, as mentioned above as a metaplasticity
mechanism that facilitates future LTP induction (Cohen et al., 1999). In
addition, (1S,3R)-ACPD was found to promote and MCPG to inhibit
epileptifom bursting (Merlin et al., 1995), in a manner that could persist
long after washout of the agonist (Merlin and Wong, 1997). These ob­
servations were suggestive of a long-lasting change in excitability but
since synaptic transmission was intact it was hard to dissect out the
relative roles of changes in synaptic and intrinsic plasticity. We observed
a long-lasting increase in neuronal burst discharges induced by DHPG or
CHPG in a Ca2+-free medium, which prevented any evoked synaptic
transmission (Thuault et al., 2002). Thus, mGluRs can trigger persistent
alterations in excitability that are independent of their effects on syn­
aptic transmission. The functional significance of mGluR-triggered
intrinsic plasticity awaits further investigation.
3.0. Concluding remarks
The development of pharmacological tools by Jeff Watkins coupled
with the rigorous pharmacological analysis by Dick Evans has led to
many key breakthroughs in the field of synaptic plasticity. In the present
article we have highlighted some of these, particularly in areas where
their work directly impacted our own. We have focused mainly on
NMDARs and mGluRs. We have described how the development of
NMDA, D-AP5 and the discovery of Mg2+ as an endogenous NMDA re­
ceptor channel blocker was so influential in the understanding of the
mechanisms of LTP, LTD and metaplasticity induction. We have also
described how the identification of (1S.3R)-ACPD and L-AP3 as the
active enantiomers of these ligands plus the development of MCPG as a
competitive mGluR antagonist resulted in a variety of novel insights into
the mechanisms of inducing and regulating synaptic plasticity. On top of
these key foundational drug developments, Jeff Watkins generated other
novel compounds that have been, or could be used, to study synaptic
plasticity (e.g., Watkins and Collingridge, 1994; Bushell et al., 1996) and
laid the foundations for David Jane to generate many more extremely
valuable ligands for the study of synaptic plasticity and other neuronal
functions in health and disease. But that’s another story.
9
Neuropharmacology 206 (2022) 108922
Acknowledgements
GLC is supported by the CIHR (Canadian Institutes of Health
Research, Foundation Grant #154276) and the Krembil Family Chair in
Alzheimer’s Research. WCA is supported by the Health Research Council
of New Zealand, #16/597 and #18/245.
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