Neuropharmacology 197 (2021) 108736

Contents lists available at ScienceDirect

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

Invited review

Mechanisms of endocannabinoid control of synaptic plasticity

Bryony Laura Winters *, Christopher Walter Vaughan
Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, University of Sydney at Royal North Shore Hospital, NSW, Australia

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

Keywords: The endogenous cannabinoid transmitter system regulates synaptic transmission throughout the nervous system.
Cannabinoids Unlike conventional transmitters, specific stimuli induce synthesis of endocannabinoids (eCBs) in the post­
Endocannabinoids synaptic neuron, and these travel backwards to modulate presynaptic inputs. In doing so, eCBs can induce short-
Synaptic plasticity
term changes in synaptic strength and longer-term plasticity. While this eCB regulation is near ubiquitous, it
displays major regional and synapse specific variations with different synapse specific forms of short-versus long-
term plasticity throughout the brain. These differences are due to the plethora of pre- and postsynaptic mech­
anisms which have been implicated in eCB signalling, the intricacies of which are only just being realised. In this
review, we shall describe the current understanding and highlight new advances in this area, with a focus on the
retrograde action of eCBs at CB1 receptors (CB1Rs).
This article is part of the special Issue on ‘Cannabinoids’.

Constituents of the plant Cannabis sativa produce many of their well-
known effects by acting on the endogenous cannabinoid transmitter
system. Over the past 30 years it has been shown that this endocanna­
binoid system acts widely throughout the nervous system. This has shed
light on the role of the endogenous cannabinoid system in various pa­
thologies and has provided leads for novel therapeutic targets. This re­
view summarises the synaptic mechanisms by which the endogenous
cannabinoid system controls brain activity, information which has
largely been obtained from the ex vivo brain slice preparation. Firstly, we
briefly describe cannabinoids and aspects of their targets which are
relevant to their synaptic actions.
1. Cannabinoids and their targets
Cannabinoids are an incredibly diverse range of plant derived, syn­
thetic and endogenous chemicals which act on a diverse range of targets.
1.1. Cannabinoids and their targets
The plant Cannabis sativa is well known for its recreational use, plus
its potential therapeutic actions and side-effects. The plant derived
constituents of cannabis include its main psychoactive constituent, Δ9-
tetrahydrocannabinol (THC), the major non-psychoactive constituent,
cannabidiol, plus over five hundred other cannabinoids, terpenes and
other natural products. There are also many synthetic drugs and
analogues of phytocannabinoids which mimic the actions of plant
derived phytocannabinoids. These include THC analogues such as
nabilone and CP55940, plus more recently characterised drugs of abuse
such as XLR-11 and AB-CHMINACA (Pertwee, 2015; Wiley et al., 2017).
The basic components of the endogenous cannabinoid system
include: endogenous molecules called endocannabinoids (eCBs),
cellular proteins involved in their production, the receptors and chan­
nels upon which they act, plus other proteins involved in their uptake
and subsequent breakdown. Of the eCBs, N-arachidonoylethanolamide
(anandamide) and 2-Arachidonoylglycerol (2-AG) are the best charac­
terised in terms of their production, targets, and degradation. Briefly,
these eCBs are largely produced ‘on demand’ from membrane bound
phospholipids in the postsynaptic cell body via an, as yet to be identified
non-vesicular manner, or potentially from non-synaptic extracellular
vesicles (Haj-Dahmane et al., 2018; Nakamura et al., 2019) (see also
section 4.1.1). Either way, eCB production differs fundamentally from
most neurotransmitters which are stored in presynaptic vesicles and
released via Ca2+-dependent and independent mechanisms.
Many of the actions of these cannabinoids are mediated by a specific
class of Gαi/o-coupled receptors, cannabinoid CB1Rs and CB2Rs, which
were identified in the 1990s (Pertwee, 2015). CB1Rs are one of the most
widely expressed Gαi/o-coupled class of G-protein coupled receptors
(GPCRs) within the nervous system, while CB2Rs are more restricted to
the immune system. Thus, CB1Rs are ideally placed to modulate synaptic
activity within the brain and thereby control a vast array of behavioural,

* Corresponding author.
E-mail address: bryony.winters@sydney.edu.au (B.L. Winters).

https://doi.org/10.1016/j.neuropharm.2021.108736
Received 29 March 2021; Received in revised form 27 July 2021; Accepted 28 July 2021
Available online 31 July 2021
0028-3908/© 2021 Elsevier Ltd. All rights reserved.
B.L. Winters and C.W. Vaughan Neuropharmacology 197 (2021) 108736

autonomic, and somatic functions. It should be noted that there is evi­
dence of cannabinoid CB2R expression within the nervous system,
particularly in pathological states (Jordan and Xi, 2019; Miller and Devi,
2011). Thus, plant derived and synthetically produced cannabinoids,
such as THC and CP55940, produce many of their effects by mimicking
the actions of eCBs at CB1Rs and/or CB2Rs. Natural, synthetic, and eCBs,
to a varying extent, also target other receptors and ion channels. These
‘non-cannabinoid receptor’ targets include GPCRs such as GPR55,
ligand gated ion channels such TRPV1, 5HT3R, GlyRs and GABAARs,
plus sodium and calcium voltage-gated ion channels (De Petrocellis
et al., 2017; Morales and Jagerovic, 2016; Muller et al., 2018).
1.2. eCB production and degradation
The eCBs anandamide and 2-AG are produced from membrane
phospholipids by distinct stimuli and biosynthetic pathways (Cascio and
Marini, 2015; Katona and Freund, 2012; Pertwee, 2015; Piomelli, 2003;
Piscitelli and Di Marzo, 2012). Anandamide is thought to be formed
from membrane phospholipids in a Ca2+ dependent manner via
NAPE-phospholipase D (PLD), PLA2 and/or other enzymes (Fig. 1). By
contrast, 2-AG is formed by Ca2+-independent
Gαq/11-GPCR/phospholipase C (PLCβ)-diacylglycerol lipase (DAGLα)
cascade and by a Ca2+-dependent PLC-DAGL pathway (Fig. 1). The ac­
tions of eCBs are terminated by their uptake via passive diffusion, or as
yet to be defined mechanisms (Fowler, 2013; Fu et al., 2011; Glaser
et al., 2003; Kaczocha et al., 2009), such as reuptake via a putative
eCB-transporter (discussed further in section 4.1.2). Once within the
cell, eCB degradation is catalysed by the enzymes, fatty acid amide
hydrolase (FAAH), monoacylglycerol lipase (MAGL), and α/β-Hydrolase
domain-containing 6/12 (ABHD6/12) (Blankman and Cravatt, 2013;
Fowler, 2012). While anandamide is largely degraded by FAAH, 2-AG is
degraded by MAGL and to a lesser extent ABHD6/12. It is also important
to note that while FAAH is mainly located postsynaptically, MAGL is
expressed in presynaptic nerve terminals. There are several recently
characterised agents which inhibit the breakdown of eCBs by FAAH and
MAGL. In doing so, these drugs can enhance the ‘natural’ activation of

Fig. 1. Endocannabinoids act as retrograde transmitters to transiently reduce the probability of neurotransmitter release. Simplified schematic depicting
the pathways involved in short-term retrograde endocannabinoid signalling. The endocannabinoid 2-arachidonylglycerol (2-AG) is generated by the conversion of
diacylglycerol into 2-AG via diacylglycerol lipase α (DAGLα). This DAGLα induced production of 2-AG can be triggered by physiological stimuli: (1) neuronal
depolarisation induced Ca2+ influx via voltage gated Ca2+ channels (VGCCs) via an unknown mechanism (2) activation of postsynaptic Gαq/11-GPCRs (e.g. group I
mGluRs, M1/3 mAChRs) by transmitters stimulates phospholipase C (PLCβ) in a Ca2+-independent manner; (3) low level Gαq/11-GPCR activation of PLCβ is enhanced
by lesser increases in Ca2+. Although its physiological origin is less clear, (4) neuronal depolarisation induced Ca2+ influx can also lead to the production of
anandamide (AEA) via enzymes such as NAPE-phospholipase D and/or phospholipase A2. (5) Following their de novo synthesis, 2-AG and AEA are then released into
the synapse, via as yet to be confirmed mechanisms. (6) These endocannabinoids ‘travel backwards’ to activate cannabinoid CB1 Gαi/o-GPCRs located on presynaptic
terminals. (7) This initiates Gβγ-subunit inhibition of presynaptic VGCCs which leads to a transient reduction in the release of neurotransmitter onto the postsynaptic
neuron which generates endocannabinoids. (8) Endocannabinoids are taken back up into neuronal and glial cells, possibly by a selective carrier-mediated transporter.
2-AG is taken up into presynaptic terminals and degraded by MAG-lipase (MAGL), while anandamide is taken up into the postsynaptic neuron and glia, then degraded
by fatty acid amide hydrolase (FAAH).

2
B.L. Winters and C.W. Vaughan
the eCB system, as opposed to receptor agonists. Together, the differ­
ential location and targets of these enzymes has consequences for the
actions of these eCBs and the therapeutic potential of FAAH and MAGL
blockers (Piscitelli and Di Marzo, 2012).
2. Short-term presynaptic actions of exogenously applied
cannabinoids
Many neurotransmitters exert their physiological effects by acting on
pre- and postsynaptic neuronal elements, and in some cases non-
neuronal elements within the nervous system. This is also the case for
cannabinoids, although the cannabinoid CB1Rs actions are largely
presynaptic.
2.1. Phytocannabinoids and synthetic cannabinoids
There is a wealth of anatomical evidence that cannabinoid CB1Rs are
largely located on presynaptic nerve terminals throughout the brain
(Ohno-Shosaku and Kano, 2014). Thus, numerous electrophysiological
studies have reported that THC and several synthetic non-selective
cannabinoid agonists produce CB1R mediated inhibition of GABAergic
and glutamatergic synaptic transmission via a presynaptic mechanism
(Alger, 2002; Araque et al., 2017; Hoffman et al., 2017; Kano et al.,
2009; Laaris et al., 2010; Schlicker and Kathmann, 2001; Shen and
Thayer, 1999) (Fig. 1). In several brain regions, however, cannabinoid
agonists inhibit GABAergic synaptic transmission with greater poten­
cy/efficacy than glutamatergic transmission. This has been attributed to
the observation that GABAergic synapses express considerably higher
levels of CB1Rs at their presynaptic terminals than their glutamatergic
counterparts (Katona et al., 2001; Marsicano and Lutz, 1999; Penasco
et al., 2019; Uchigashima et al., 2007) although see (Katona et al.,
2006). It should be emphasised that cannabinoid receptors are also
expressed in non-neuronal elements where they have complex actions;
this is addressed in another review in this issue.
The presynaptic nature of cannabinoid inhibition has been delin­
eated by using a variety of electrophysiological techniques such as the
examination of paired evoked synaptic currents, quantal TTX-resistant
synaptic currents, and presynaptic calcium imaging. It has generally
been assumed that voltage-gated calcium channels (VGCCs) have a
crucial role in the modulation of synaptic transmission by cannabinoids
because Ca2+ entry into the nerve terminal is required for presynaptic
vesicle fusion and the subsequent release of neurotransmitter (see
Gandini and Zamponi, 2021; Zamponi and Currie, 2013 for compre­
hensive reviews on GPCR modulation of VGCCs). Accordingly, CB1R
activation inhibits VGCCs and reduces the influx of Ca2+ into presyn­
aptic nerve terminals (Daniel and Crepel, 2001; Kreitzer and Regehr,
2001; Twitchell et al., 1997) (Fig. 1). In addition, cannabinoid
agonist-induced inhibition of synaptic transmission is reduced by
blockade of N- and P/Q-type VGCCs (Hoffman and Lupica, 2000; Huang
et al., 2003; Sullivan, 1999; Varma et al., 2002). Indeed, it has been
shown that presynaptic CB1R induced inhibition via VGCCs is mediated
via the Gβγ, rather than the Gαi/o subunit (Jensen et al., 2021; Roloff and
Thayer, 2009) (Fig. 1). While it has been shown that cannabinoid re­
ceptors couple more directly to presynaptic release mechanisms, there
are several other less direct presynaptic mechanisms (Robbe et al.,
2003). It has been demonstrated that presynaptic 4-AP sensitive
K+-channels have a role in cannabinoid CB1R induced inhibition (Daniel
and Crepel, 2001; Robbe et al., 2003; Varma et al., 2002). Mitochondrial
CB1Rs have a role in cannabinoid inhibition of glutamatergic synaptic
transmission in the hippocampus via soluble adenylyl cyclase-protein
kinase A (PKA) control of mitochondrial energetic activity (Hebert-Ch­
atelain et al., 2016). Finally, while the probability of neurotransmitter
release can also be controlled by the size of the ready releasable pool of
vesicles, there are conflicting reports as to whether this is modulated by
cannabinoids (García-Morales et al., 2015; Sullivan, 1999).
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Neuropharmacology 197 (2021) 108736
2.2. Endocannabinoids
Numerous studies have demonstrated that exogenous application of
the eCBs, anandamide, and 2-AG, presynaptically inhibits synaptic
transmission within a number of regions throughout the brain and spinal
cord. However, there are regional and synapse specific variations. In
some brain regions anandamide inhibits GABAgeric, but not gluta­
matergic synaptic transmission while synthetic agonists inhibit both
GABAergic and glutamatergic synaptic transmission (Adermark and
Lovinger, 2007b; Hentges, 2007; Hentges et al., 2005; Jennings et al.,
2001, 2003; Kawahara et al., 2011; Lau et al., 2014). These differences
are likely to be due to several factors, in addition to the level of CB1R
expression between excitatory and inhibitory synapses described above
(Shen et al., 1996). Firstly, synthetic cannabinoid agonists generally
have greater efficacy and potency at cannabinoid receptors than eCBs.
Secondly, eCBs undergo uptake and breakdown which greatly limits
their access to the synapse following exogenous administration. Thus,
the anandamide and 2-AG induced inhibition of synaptic transmission is
enhanced by blocking their degradation with FAAH and MAGL in­
hibitors, respectively (Bajo et al., 2009; Kawahara et al., 2011; Lau et al.,
2014; Lee et al., 2015; Vaughan et al., 2000; Yasmin et al., 2020).
Another potential factor is that anandamide acts at other presynaptic
targets within the brain, such as the non-selective cation channel,
TRPV1 (Marinelli et al., 2002, 2003), plus a range of postsynaptic ele­
ments (section 1.1). Thus, TRPV1 mediated enhancement of synaptic
transmission functionally opposes CB1R mediated inhibition (Bhaskaran
and Smith, 2010; Kawahara et al., 2011; Lee et al., 2015; Morisset et al.,
2001). In addition to these factors, anandamide enhances presynaptic
excitability via intracellular cascades involving PKA and IP3 (Hofmann
et al., 2011; Sang et al., 2010).
2.3. Tonic presynaptic endocannabinoid control
In addition to their actions following exogenous administration,
tonically released eCBs exert a basal presynaptic CB1R mediated sup­
pression of GABAergic, and to a lesser extent, glutamatergic synaptic
transmission in several brain regions. In these studies, it has been
demonstrated that CB1R antagonists, such as rimonabant (SR141716)
and AM251, produce an increase in evoked and spontaneous TTX-
resistant synaptic currents in the slice preparation, and even in iso­
lated neurons with intact presynaptic boutons (Ferraro et al., 2020;
Hentges et al., 2005; Huang and Woolley, 2012; Lau et al., 2014;
Losonczy et al., 2003; Manz et al., 2020; Marcus et al., 2020; Melis et al.,
2004a; Neu et al., 2007; Oliet et al., 2007; Song et al., 2015; Yasmin
et al., 2020; Zhu and Lovinger, 2005). This tonic suppression is likely to
be due to postsynaptic release of eCBs because it is blocked by chelating
postsynaptic Ca2+ with BAPTA (Hentges et al., 2005; Losonczy et al.,
2003; Manz et al., 2020; Neu et al., 2007; Oliet et al., 2007; Zhu and
Lovinger, 2005). It is also likely that the tonic suppression is related to
the basal excitability of neurons because it can be enhanced by
increasing neuronal firing (Drew et al., 2008; Lee et al., 2010; Oliet
et al., 2007; Song et al., 2015). Thus, the level of the basal ‘endo­
cannabinoid tone’ maybe be reflected by the overall level of neuronal
excitability in different brain regions and experimental conditions.
Interpretation of these tonic eCB experiments is, however, compli­
cated because cannabinoid ligands such as rimonabant and AM251 are
inverse agonists. Indeed, a role for constitutive CB1R activation has been
demonstrated in the hippocampus because while basal GABAergic syn­
aptic transmission is enhanced by AM251, it is unaffected by the neutral
antagonist NESS0327 (Jensen et al., 2021; Lee et al., 2015). Recently, it
has been shown that this constitutive activity is mediated by the Gβγ
subunit of CB1Rs (Jensen et al., 2021). By contrast, in some regions, such
as the midbrain PAG and prefrontal cortex both inverse CB1R agonists
and neutral CB1R antagonists enhance synaptic transmission, indicating
that tonic inhibition is due to the release of eCBs which are acting on
CB1Rs (Lau et al., 2014; Marcus et al., 2020).
B.L. Winters and C.W. Vaughan
The activity of the eCBs is tightly regulated by their uptake and
degradation via FAAH and MAGL (Blankman and Cravatt, 2013; Di
Marzo, 2018; Fowler et al., 2017). A number of studies have demon­
strated that tonic suppression of synaptic transmission can be unmasked,
or enhanced by blocking the metabolism of eCBs, using selective in­
hibitors of FAAH (e.g. URB597, PF3845) and MAGL (e.g. JZL184), or
genetic deletion of these enzymes (Ferraro et al., 2020; Kawahara et al.,
2011; Lau et al., 2014; Lee et al., 2010, 2015; Liu et al., 2016; Yasmin
et al., 2020). However, there are substantial regional and synapse spe­
cific variations in the relative roles of these enzymes, in addition to
gender and species related differences. In some cases, dual blockade of
both FAAH and MAGL (e.g. with JZL195) leads to a greater increase in
tonic inhibition of synaptic transmission than individual blockade of
FAAH, or MAGL (Fucich et al., 2020; Lau et al., 2014). This indicates
that 2-AG and anandamide are tonically released, and that their actions
can be enhanced by overcoming their uptake and breakdown with
FAAH/MAGL inhibitors. It should also be noted that, in some regions,
MAGL has been reported to make a greater contribution to tonic sup­
pression than FAAH, and this has been attributed to functionally
opposing pre- and postsynaptic actions of anandamide on TRPV1
channels (Kawahara et al., 2011; Lee et al., 2015).
3. Short-term synaptic plasticity
It is now well established that eCBs act as retrograde messengers
throughout the brain. Unlike most neurotransmitters, they are produced
‘on-demand’ in the postsynaptic neuron and travel backwards to control
the release of neurotransmitters onto that neuron. Generally, this short-
term depression is expressed by activation of presynaptic CB1Rs.
Following is a summary of the mechanisms underlying short-term eCB
induced plasticity.
3.1. The triggers for retrograde eCB signalling
Retrograde eCB signalling can be induced by the engagement of a
range of distinct postsynaptic voltage/ligand gated ion channels and
receptors. These are discussed below.
3.1.1. Neuronal depolarisation
The first evidence for a physiological role for eCBs was based on the
phenomenon of ‘depolarisation-induced suppression of inhibition’
(DSI), previously observed in the hippocampus and cerebellum (Fig. 1).
In these intriguing studies, brief (seconds) postsynaptic depolarisation
produced a short-lasting inhibition of transmitter release onto that
neuron, observed as inhibition of electrically evoked GABAergic inhib­
itory postsynaptic currents (IPSCs) (Llano et al., 1991; Pitler and Alger,
1992). It was not until a decade later that eCBs were identified as the
retrograde signalling agent involved in DSI, and the parallel phenome­
non of ‘depolarisation-induced suppression of excitation’ (DSE, for
glutamatergic excitatory postsynaptic currents, EPSCs), both in brain
slice and cultured neuron preparations (Diana et al., 2002; Kreitzer and
Regehr, 2001; Ohno-Shosaku et al., 2001; Wilson and Nicoll, 2001).
Briefly, the key observations which identified eCBs as retrograde
signalling agents in this form of short-term plasticity are:
A. Postsynaptic induction: The depolarisation induced reduction in
evoked synaptic currents is abolished by rapid buffering of post­
synaptic Ca2+ with BAPTA, while that produced by cannabinoid
CB1R agonists is unaffected by postsynaptic BAPTA. Furthermore,
the depolarisation induced inhibition is associated with an increase
in postsynaptic Ca2+ and this is abolished by subtype selective VGCC
blockers. Thus, DSI and DSE are generated by a depolarisation
induced postsynaptic Ca2+ influx via VGCCs.
B. Presynaptic expression: Depolarisation produces (i) an increase in the
paired pulse ratio and co-efficient of variation of electrically evoked
synaptic currents, (ii) an increase in failure rate of synaptic currents
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Neuropharmacology 197 (2021) 108736
evoked by minimal stimulation, (iii) a reduction in the frequency,
but not amplitude of spontaneous TTX-resistant, or evoked Sr2+-
mediated quantal synaptic currents, but (iv) does not affect the
current induced by exogenous application of the modulated trans­
mitter, GABA or glutamate. Thus, postsynaptic depolarisation pro­
duces a presynaptic reduction in the probability of release of that
neurotransmitter from nerve terminals impinging upon that neuron.
C. Mediated by eCBs: The depolarisation induced reduction in evoked
synaptic currents is (i) abolished by CB1R antagonism and knockout,
(ii) unaffected by blocking vesicular endocytosis with postsynaptic
botulinum neurotoxin (Wilson and Nicoll, 2001), and (iii) is abol­
ished by disrupting postsynaptic signalling pathways involved in the
production of eCBs (see below). Thus, retrograde eCB signalling in­
volves ‘on-demand’ postsynaptic production and non-vesicular
release of eCBs.
Since these initial studies, depolarisation induced retrograde sig­
nalling has been detected in numerous brain regions. Some of these
regions include the amygdala (Kamprath et al., 2011; Kodirov et al.,
2010; Zhu and Lovinger, 2005), dorsal raphe nucleus (Haj-Dahmane and
Shen, 2009), cortex (Bodor et al., 2005; Fortin et al., 2004; Marcus et al.,
2020; Terral et al., 2020), habenula (Vickstrom et al., 2020), hypo­
thalamus (Colmers and Bains, 2018; Hirasawa et al., 2004; Jo et al.,
2005), striatum (Uchigashima et al., 2007), substantia nigra (Wall­
michrath and Szabo, 2002; Yanovsky et al., 2003), and ventral
tegmental area (Melis et al., 2004b).
3.1.2. G-protein coupled receptors
Following on from the phenomenon of DSI/DSE, it was shown that
short-term retrograde eCB plasticity could also be induced by activation
of postsynaptic Gαq/11-coupled group 1 metabotropic glutamate
(mGluR) and M1/M3 Gαq/11-coupled cholinergic muscarinic receptors
(M1/M3 mAChRs) in the hippocampus and cerebellum (Kim et al., 2002;
Maejima et al., 2001; Varma et al., 2001) (Fig. 1). A parallel experi­
mental approach to that described above for depolarisation-induced
suppression demonstrated Gαq/11-GPCR induced suppression was
mediated by retrograde eCB signalling. The postsynaptic locus of in­
duction was demonstrated by the observation that postsynaptic GDPβS
abolished the inhibition produced by group 1 mGluR and mAChR ago­
nists, but not that produced by cannabinoid agonists which act directly
on presynaptic CB1Rs.
Since these initial studies in the hippocampus and cerebellum, group
1 mGluR-induced, retrograde eCB signalling has been shown to occur at
numerous GABAergic and glutamatergic synapses throughout the brain.
Some of these regions include the amygdala (Sheinin et al., 2008; Zhu
and Lovinger, 2005), calyx of Held (Kushmerick et al., 2004), cortex
(Kiritoshi et al., 2016), hypothalamus (Iremonger et al., 2011), midbrain
periaqueductal grey (Drew et al., 2008), striatum (Centonze et al., 2007;
Kreitzer and Malenka, 2005; Narushima et al., 2006), substantia nigra
(Freestone et al., 2014), and ventral tegmental area (Melis et al., 2004a).
It should be noted that the relative role of the postsynaptic group 1 re­
ceptor subtypes, mGluR1 and mGluR5, in retrograde eCB signalling
varies throughout the brain. In addition to this, agonist induced acti­
vation of postsynaptic M1/M3 Gαq/11-coupled mAChRs has also been
shown to induced retrograde eCB inhibition of synaptic transmission in
several brain regions (Edwards et al., 2006; Freestone et al., 2015;
Fukudome et al., 2004; Lau and Vaughan, 2008; Martin et al., 2015;
Narushima et al., 2006; Neuhofer et al., 2018).
Activation of the retrograde eCB signalling system is not exclusive to
metabotropic glutamate and cholinergic receptors. Several other classes
of neurotransmitter-GPCR systems have been shown to inhibit
GABAergic and glutamatergic synaptic transmission via retrograde eCB
signalling. Some of these transmitter-GPCR systems include cholecys­
tokinin-CCK1R (Földy et al., 2007; Mitchell et al., 2011), dopamine-D2R
(Yin and Lovinger, 2006), neurotensin-NT1/2R (Kortleven et al., 2012;
Mitchell et al., 2009; Yin et al., 2008), orexin-OX1/2R (Haj-Dahmane and
B.L. Winters and C.W. Vaughan
Shen, 2005; Ho et al., 2011; Kargar et al., 2018; Tung et al., 2016),
oxytocin-OTR (Hirasawa et al., 2004; Oliet et al., 2007), seroto­
nin-5HT2R (Best and Regehr, 2008), and substance P-NK1/2R (Drew
et al., 2009). However, several lines of evidence indicate that some of
these neurotransmitters do not directly engage the eCB system by their
respective postsynaptic receptors. Firstly, the cholecystokinin, neuro­
tensin, and substance P induced inhibition of evoked synaptic currents is
abolished, not only by cannabinoid receptor antagonists, but also by
group 1 mGluR antagonists in the striatum and midbrain periaqueductal
grey (Drew et al., 2009; Mitchell et al., 2009, 2011; Yin et al., 2018).
Secondly, while these transmitters produce an increase in the
paired-pulse ratio of evoked synaptic currents, they do not inhibit the
rate of spontaneous (Ca2+-dependent and -independent) miniature
synaptic currents. This suggests that these peptides act upstream to the
cannabinoid-sensitive synapse (Drew et al., 2009; Mitchell et al., 2009,
2011). Together, these observations indicate that these neurotransmit­
ters increase the release of glutamate, which then engages postsynaptic
mGluR-induced retrograde eCB signalling.
Other classes of receptors can also drive eCB retrograde inhibition.
For example, the inhibition of synaptic transmission induced by BDNF
(via the tyrosine kinase TrkB receptor), glucocorticoids and estrogen
(via glucocorticoid and E-alpha nuclear receptors) is mediated by
retrograde eCB signalling (Di et al., 2003; Huang and Woolley, 2012;
Tabatadze et al., 2015; Wu et al., 2020; Yeh et al., 2017). As for some of
the above Gαq/11-coupled receptors, however, the inhibition of synaptic
transmission by estrogen has been shown to be via mobilisation of
postsynaptic mGluR receptors (Huang and Woolley, 2012).
3.1.3. G-protein coupled receptor and depolarisation induced interactions
In addition to their individual actions, there are interactions between
Gαq/11-receptor and depolarisation induced retrograde eCB inhibition.
In the hippocampus, sub-threshold concentrations of mGluR1/5 and M1/3
mAChR agonists potentiate DSI and DSE (Hoffman et al., 2003; Kim
et al., 2002; Ohno-Shosaku et al., 2002a, 2003; Varma et al., 2001).
Gαq/11-induced interactions have since been observed for mGluR,
mAChR and D1Rs in the amygdala, substantia nigra and ventral
tegmental area (Kiritoshi et al., 2016; Tong et al., 2017; Yanovsky et al.,
2003). There are some interesting drug targets which can be used to
enhance the natural engagement of the Gαq/11-receptor eCB system and
its enhancement of depolarisation-induced signalling. For example, in
some regions mGluR5 negative allosteric modulators reduce DSI/DSE,
indicating that there is tonic mGluR-driven eCB signalling (Kiritoshi
et al., 2013; Straiker et al., 2018). Thus, besides directly acting agonists,
DSI and DSE can be enhanced by an mGluR5 positive allosteric modu­
lator, or by knockout of SAP90/PSD-95-associated proteins, both of
which enhance mGluR5 expression/signalling (Chen et al., 2011; Kir­
itoshi et al., 2016) see also section 4.1.1).
3.1.4. Ligand gated ion channels (LGIC)
In addition to depolarisation induced Ca2+ increases via VGCCs, it
has also been shown that eCB signalling can be induced by a range of
Ca2+-permeable ligand gated ion channels. These include ionotropic
glutamate receptors, such as NMDA receptors (NMDAR), kainite re­
ceptors and Ca2+-permeable AMPA receptors (Lourenço et al., 2011;
Manz et al., 2020; Marshall et al., 2018; Ohno-Shosaku et al., 2007)
(Fig. 1). Furthermore, activation of TRPV1 has been shown to induce
retrograde eCB inhibition of synaptic transmission in the periaqueductal
grey (Liao et al., 2011). However, this is indirectly mediated by TRPV1
enhancement of glutamate release, activation of postsynaptic mGluRs
and retrograde CB1R inhibition of GABAergic synaptic transmission, as
described above for cholecystokinin.
3.1.5. Retrograde eCB signalling is heterogeneous and is engaged by
physiological stimuli
While retrograde eCB signalling is observed in numerous brain re­
gions, it is not an ubiquitous, homogenous phenomenon. While
5
Neuropharmacology 197 (2021) 108736
presynaptic sensitivity is a major determinant of depolarisation-induced
suppression at some synapses (Ohno-Shosaku et al., 2002b), DSI/DSE
are weak, or absent in some cannabinoid-sensitive synapses (Drew et al.,
2008; Engler et al., 2006; Freiman et al., 2006; Hentges et al., 2005;
Kreitzer and Malenka, 2005; Sheinin et al., 2008). This heterogeneity
may be more widespread than currently thought because the use of gross
electrical stimulation to examine synaptic transmission can mask syn­
apse specific differences. Thus, the use of minimal stimulation, paired
recordings, and optogenetic approaches to activate specific synaptic
inputs has revealed an increasing diversity in the actions of endoge­
nously released cannabinoids (Colmers and Bains, 2018; Deroche et al.,
2020; Lines et al., 2017; Wilson and Nicoll, 2001). In addition to
‘normal’ variations, it might be noted that the presence and extent of
retrograde eCB signalling can be altered in pathological states (Di et al.,
2013; Kiritoshi et al., 2016; Marcus et al., 2020).
Most of the above studies have used stimuli which are less physio­
logically relevant to engage retrograde eCB signalling, such as prolonged
depolarisation and application of synthetic GPCR/LGIC agonists. How­
ever, several studies have shown that eCB signalling can be driven by
physiologically relevant stimuli. Depolarisation induced retrograde
signalling can be induced by postsynaptic action potential firing at
physiological rates, at least in some brain regions (Dubruc et al., 2013;
Fortin et al., 2004). Likewise, group 1 mGluR signalling can be induced
in some brain regions by stimulation of glutamatergic afferent inputs at
physiologically relevant rates (Brown et al., 2003; Chen et al., 2016;
Galante and Diana, 2004; Maejima et al., 2001; Marcaggi and Attwell,
2005; Melis et al., 2004a; Yin and Lovinger, 2006).
3.2. Postsynaptic signalling mechanisms involved in short-term plasticity
The postsynaptic mechanisms involved in short-term retrograde eCB
signalling have been driven by our understanding of the pathways
involved in their production and degradation (section 1.1). Kano and
colleagues have categorised short-term eCB plasticity induced by the
above triggers into three basic signalling modes: (i) Ca2+-dependent
signalling which is induced by depolarisation, (ii) Ca2+-independent
signalling which is induced by Gαq/11-coupled GPCRs, and (iii) Ca2+-
assisted signalling which is induced by an interaction between depo­
larisation and Gαq/11-coupled GPCRs (Fig. 1) (Araque et al., 2017;
Castillo et al., 2012; Kano et al., 2009; Katona and Freund, 2012;
Ohno-Shosaku and Kano, 2014). These are described below.
3.2.1. Ca2+-dependent eCB signalling
The postsynaptic signalling pathways underlying depolarisation-
induced retrograde inhibition have only been partly resolved.
Depolarisation-induced retrograde eCB signalling requires a large in­
crease in postsynaptic Ca2+ to micromolar levels (Fig. 1). Thus, both DSI
and DSE can be mimicked by uncaging postsynaptic Ca2+ and abolished
by chelating postsynaptic Ca2+ with BAPTA (Kim et al., 2002; Kreitzer
and Regehr, 2001; Ohno-Shosaku et al., 2001; Pitler and Alger, 1992;
Trettel and Levine, 2003; Wilson and Nicoll, 2001). The main source of
postsynaptic Ca2+ for DSI and DSE is entry via L-type VGCCs triggered
by neuronal depolarisation, although release from intracellular Ca2+
stores has also been reported to have a role in some regions (Isokawa and
Alger, 2005; Straiker and Mackie, 2005) (Fig. 1).
The eCB involved in depolarisation-induced retrograde eCB signal­
ling is likely to be 2-AG because it is prolonged by blockade and
knockout of MAGL, but not FAAH in numerous brain regions (Hashi­
motodani et al., 2007b; Kiritoshi et al., 2016; Makara et al., 2005;
Marcus et al., 2020; Straiker and Mackie, 2005; Szabo et al., 2006;
Vickstrom et al., 2020). While native expression of FAAH does appear to
have a role DSI and DSE, it has been shown that overexpression of FAAH
can influence hippocampal DSE in cultured neurons (Straiker et al.,
2011; Zimmermann et al., 2019). There is also some evidence of a role
for COX-2 and ABHD6 in the control of DSI and DSE (Kim and Alger,
2004; Kiritoshi et al., 2016; Straiker et al., 2009; Zhong et al., 2011).
B.L. Winters and C.W. Vaughan
While 2-AG can be formed by the PLC-DAGL cascade, the specific
signalling cascade underlying depolarisation-induced production of 2-
AG remains unclear (Fig. 1). DSI and DSE are unaffected by the PLC
inhibitors U73122 and ET18 (Brenowitz and Regehr, 2003; Chevaleyre
and Castillo, 2003; Edwards et al., 2006; Hashimotodani et al., 2008;
Szabo et al., 2006), or by knockout of PLCβ1/4 and PLCδ1/3/4
(Hashimotodani et al., 2005; Maejima et al., 2005). By contrast, DSI and
DSE are abolished by the DAGL inhibitors tetrahydrolipstatin and
RHC80267 (Kano et al., 2009), and this has been confirmed more
recently with a more selective DAGL inhibitor, DO34, and knockout of
DAGLα (Gao et al., 2010; Hashimotodani et al., 2013; Marcus et al.,
2020; Tong et al., 2017; Vickstrom et al., 2020; Wang et al., 2012;
Yoshino et al., 2011). Furthermore, the threshold for
depolarisation-induced suppression is correlated to the level of DAGL
expression (Yoshida et al., 2011). Together, these observations indicate
that DSI and DSE are mediated by an unknown PLCβ-independent
pathway which involves DAGLα dependent production of 2-AG. There
are potential alternative pathways for depolarisation-induced eCB sig­
nalling. It has recently been shown that activation of PLCε by the ex­
change protein directly activated by cAMP (Epac) induces DSI in the
VTA (Tong et al., 2017). It has also been shown that DSE is abolished by
knockout of cytosolic PLA2 and DAGL in the cerebellum (Wang et al.,
2012). However, the role of the enzymes, PLCε and PLA2, remains to be
verified.
In addition to direct postsynaptic neuronal depolarisation, several
ligand-gated ion channels have been shown to induce retrograde eCB
signalling (section 3.1.3). Indeed, kainite, NMDA and Ca2+-permeable
AMPA receptor-induced retrograde eCB signalling, which is Ca2+-
dependent because it is blocked by postsynaptic BAPTA (Lourenço et al.,
2011; Manz et al., 2020; Marshall et al., 2018; Ohno-Shosaku et al.,
2007) (Fig. 1). There are, however, some differences. In two of these
studies, the kainite and Ca2+-permeable AMPA receptor induced inhi­
bition appears to be mediated by anandamide, rather than 2-AG because
it is prolonged by URB597, but not by JZL184, and is unaffected by
DAGL inhibitors (Lourenço et al., 2011; Manz et al., 2020). In the other
study, kainite and NMDA receptor induced inhibition involves DAGL
(Marshall et al., 2018; Ohno-Shosaku et al., 2007). The relative roles of
anandamide and 2-AG in these forms of retrograde signalling, and their
signalling pathways remain to be verified.
3.2.2. Ca2+-independent eCB signalling
The postsynaptic signalling pathways underlying Gαq/11-receptor
induced retrograde inhibition of synaptic transmission have been well
characterised in numerous brain regions (Fig. 1). Firstly, mGluR1/5 and
M1/3 mAChR induced inhibition is G-protein mediated because it is
abolished by postsynaptic GDPβS in the hippocampus and cerebellum
(Galante and Diana, 2004; Kim et al., 2002; Maejima et al., 2001, 2005;
Neu et al., 2007). These studies have also shown that mGluR/mAChR
induced inhibition is Ca2+-independent because it is unaffected by
postsynaptic BAPTA. This coupling has also been observed for retro­
grade eCB signalling in other brain regions, and for a range of
Gαq/11-coupled GPCRs (for reference, see studies described in section
3.1.2). It might be noted, however, that Ca2+-dependent coupling has
been observed in some preparations which involves the release of Ca2+
from intracellular stores (Melis et al., 2004a; Robbe et al., 2002; Straiker
and Mackie, 2005).
Like DSI and the DSE, the eCB involved in Gαq/11-coupled GPCR
induced retrograde inhibition is also likely to be 2-AG because Gαq/11
agonist induced inhibition is prolonged by blockade and knockout of
MAGL, but not FAAH (Kiritoshi et al., 2016; Selvam et al., 2018; Tung
et al., 2016; Zhong et al., 2011). It is well known that Gαq/11-GPCRs,
such as group 1 mGluRs, activate PLCβ which hydrolyses membrane
phospholipids to produce inositol 1,4,5-trisphosphate (IP3) and 1,2-diac­
ylglycerol (DAG), the latter of which is then converted by DAGL into
2-AG (section 1.1) (Fig. 1). Despite some earlier controversies (Kano
et al., 2009), more recent pharmacological and knockout studies have
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Neuropharmacology 197 (2021) 108736
demonstrated that both PLCβ and DAGLα are involved in Gαq/11-induced
retrograde eCB signalling in several brain regions (Chen et al., 2016;
Hashimotodani et al., 2013; Ho et al., 2011; Kargar et al., 2018; Kortl­
even et al., 2012; Lau and Vaughan, 2008; Maejima et al., 2005; Melis
et al., 2004a; Selvam et al., 2018; Sheinin et al., 2008; Tanimura et al.,
2010; Tung et al., 2016; Wu et al., 2020; Zhong et al., 2011). Together,
these studies indicate that Gαq/11-receptor induced retrograde eCB sig­
nalling is mediated by Ca2+-independent production of 2-AG via a
PLCβ-DAGLα pathway.
3.2.3. Ca2+-assisted eCB signalling
The postsynaptic signalling pathways underlying Gαq/11-receptor
induced enhancement of depolarisation induced retrograde inhibition of
synaptic transmission have been characterised (Fig. 1). The mechanisms
underlying this synergistic interaction slightly differ to those involved in
Gαq/11-induced eCB signalling. Like Gαq/11-receptor induced eCB sig­
nalling, the Gαq/11-induced enhancement of DSI/DSE involves the PLCβ-
DAGLα cascade as it is abolished by their knockout (Hashimotodani
et al., 2005; Maejima et al., 2005). Unlike Gαq/11-receptor induced eCB
signalling, the Gαq/11-induced enhancement of DSI/DSE is a
Ca2+-dependent process. This has been demonstrated by the correlation
between the degree of enhancement with the intracellular level of
free-Ca2+, and the role of PLCβ by knockout. Thus, PLCβ acts to integrate
different forms of eCB signalling, including those triggered by
Gαq/11-coupled receptors and neuronal depolarisation. Finally, other
interactions between eCB signalling systems have been observed. For
example, Gαi/o-coupled D2R actions enhance DSI and DSE (Melis et al.,
2004b). It remains to be seen whether other neurotransmitters systems
interact with eCBs.
3.3. Termination of short-term plasticity
Short-term retrograde endocannabinoid signalling is temporally
restricted and spatially confined to the postsynaptic neurons where they
are produced, and in some cases, adjacent synapses (Galante and Diana,
2004; Kreitzer et al., 2002; Maejima et al., 2001; Wilson and Nicoll,
2001). This temporal and spatial restriction is influenced not only by the
fate of endocannabinoids, but also by that of the neurotransmitters
driving their production.
3.3.1. eCB uptake and degradation
Basal and stimulus-evoked eCB signalling are controlled by the lipid
nature of eCBs which limits their spread in the extracellular environ­
ment, and by the uptake and breakdown of eCBs which limits their
temporal and spatial activity (Fig. 1). As noted above, degradation via
both enzymes FAAH and MAGL limits basal eCB inhibition in some brain
regions (section 2.3). By contrast, degradation via the enzyme MAGL
limits depolarisation and Gαq/11-receptor induced retrograde eCB inhi­
bition, both temporally and spatially (sections 3.2.1 and 3.2.2). This
breakdown has a crucial physiological role because MAGL inhibition
and knockout greatly enhance mGluR-mediated retrograde inhibition
elicited by ‘physiological’ stimulation evoked glutamate release (Chen
et al., 2016; Kiritoshi et al., 2016; Zhong et al., 2011). Using cell-specific
knockout, it has been shown that both neuronal and glial MAGL control
retrograde eCB signalling within both the cerebellum and hippocampus,
although their relative contributions vary with different synapses (Chen
et al., 2016; Liu et al., 2016; Viader et al., 2015). Interestingly, the up­
take and degradation of eCBs can be altered in pathological states which
affect glia (and consequently their uptake of endocannabinoids) and
levels of eCB breakdown enzymes (Di et al., 2013; Longaretti et al.,
2020). It has therefore been suggested that inhibitors of endocannabi­
noid degradation are likely to have important implication for numerous
diseases and disorders (Cristino et al., 2020; Fowler, 2015; Senst and
Bains, 2014).
B.L. Winters and C.W. Vaughan
3.3.2. Glutamate uptake and degradation
Activation of Gαq/11-coupled retrograde endocannabinoid signalling,
such as that by group 1 mGluRs, is also controlled by the uptake of
glutamate. Normally, the spread of glutamate is tightly controlled by
transporters, but spill-over from the synaptic cleft can lead to an
enhancement and spread of mGluR induced eCB mediated inhibition.
This spill-over can be caused by concurrent activation of nearby (rather
than spatially dispersed) synapses which overwhelms glutamate trans­
porters at those synapses. It can also be promoted by drugs which inhibit
neuronal and/or glial glutamate transporters (Crepel and Daniel, 2007;
Drew et al., 2008; Freestone et al., 2014; Linehan et al., 2018; Marcaggi
and Attwell, 2005). A similar enhancement of mAChR induced retro­
grade endocannabinoid signalling has been observed with cholines­
terase inhibitors (Lau and Vaughan, 2008; Narushima et al., 2007).
4. Long-term synaptic plasticity
In addition to short-term changes in synaptic strength, it is now well
established eCBs play a central role in the induction of bidirectional
long-term synaptic plasticity. Long-term potentiation (LTP) and long-
term depression (LTD) are two major forms of long-lasting plasticity
that describe the activity-dependent strengthening or weakening of
synaptic efficacy (respectively). They can be induced by diverse patterns
of activity and unlike short-term plasticity, which results from a tran­
sient signal that does not overtly change synaptic architecture, long-
term plasticity is maintained by changes in the presynapse (e.g.
release machinery) or postsynapse (e.g. receptor surface expression) or
both, which fundamentally alters synaptic connectivity. This persistent
change in synaptic efficacy can last several hours or days. It is a brain-
wide phenomenon that is critical for experience-dependent adaptions
of neural circuits, which can underlie a plethora of processes ranging
from learning and memory formation to complex behavioural adaptions
to environmental stimuli (see Chistiakova and Volgushev, 2009; Citri
and Malenka, 2008; Collingridge et al., 2004; Yang and Calakos, 2013
for comprehensive reviews on synaptic plasticity).
eCBs play a major role in regulating long-term plasticity and are
necessary for the induction of several forms LTP and LTD (Araque et al.,
2017; Castillo et al., 2012; Piette et al., 2020). This has been demon­
strated in numerous regions within the CNS including: the hippocampus
(Chevaleyre and Castillo, 2003), striatum (Gerdeman et al., 2002),
amygdala (Azad et al., 2004), nucleus accumbens (Robbe et al., 2002),
nucleus tractus solitarius (Khlaifia et al., 2013), ventral tegmental area
(Friend et al., 2017), cerebellum (Soler-Llavina and Sabatini, 2006),
several cortical regions (e.g. prefrontal, Martin et al., 2015; somato­
sensory, Bender et al., 2006; visual, Joo et al., 2019 & insular, Liu et al.,
2013; cortices) and the spinal cord (Kato et al., 2012). In addition, eCBs
have been implicated in metaplasticity (the plasticity of plasticity;
Chevaleyre and Castillo, 2004; Jensen et al., 2021; Melis et al., 2014; Xu
et al., 2014; Yang et al., 2014); and synaptic scaling (Kim and Alger,
2010; Zhang et al., 2009), both of which are powerful homeostatic
processes that can set the gain of network activity and govern associative
information processing (Abraham, 2008; Turrigiano, 2008). eCBs can
therefore have a long-term impact on neuronal function in numerous
brain regions and accordingly, eCBs have been linked to multiple pro­
cesses including: learning and memory, goal-directed/habitual decision
making, sensory processing, motor control and feeding behaviours
(reviewed in Augustin and Lovinger, 2018).
Like short-term plasticity, eCB-dependent long-term plasticity
(henceforth referred as eCB-plasticity) is primarily a postsynaptically
induced but presynaptically expressed phenomenon (Azad et al., 2004;
Carey et al., 2011; Chevaleyre and Castillo, 2003; Gerdeman et al., 2002;
Wilson and Nicoll, 2001). Through their retrograde action, eCBs that are
released from the postsynapse, act on presynaptic CB1Rs to initiate a
Gαi/o-signalling cascade that persistently reduces the probability of
neurotransmitter release via diverse mechanisms (discussed in detail
below). Since this is fundamentally an inhibitory process that reduces
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Neuropharmacology 197 (2021) 108736
synaptic efficacy, the direction of plasticity depends on the type of
presynaptic input being stimulated and whether there is a homo- or
hetero-synaptic contribution. For instance, eCB-LTP is primarily a form
of heterosynaptic or metaplastic plasticity in which potentiation is
facilitated by the long-lasting disinhibition of excitatory synapses
attributed to eCB-mediated LTD of inhibitory inputs (iLTD; Basu et al.,
2013; Chevaleyre and Castillo, 2003, 2004; Kim et al., 2019; Monory
et al., 2015; Xu et al., 2012; Younts et al., 2013; Zhu and Lovinger,
2007). It should be noted however, recent evidence indicates eCB-LTP
can also be homosynaptic with eCBs acting at either TRPV1s or CB1Rs
(Cui et al., 2015; Cui et al., 2018; Wang et al., 2016 & see section 4.3.1).
In contrast, eCB-LTD may be homo- or heterosynaptic and can be
expressed at both glutamatergic and GABAergic synapses (Adermark
et al., 2009; Arami et al., 2013; Chevaleyre and Castillo, 2003; Chiu
et al., 2010; Penasco et al., 2019; Peterfi et al., 2012). However, given
the frequent requirement for Gαq/11-coupled signalling, eCB-plasticity at
GABAergic synapses is often heterosynaptic, although some evidence
indicates strong repetitive postsynaptic depolarisation is sufficient to
induce homosynaptic eCB-plasticity at GABAergic synapses in the hip­
pocampus (Younts et al., 2013). In addition to retrograde signalling,
eCBs act in an autocrine manner at postsynaptic CB1Rs or TRPV1s to
induce LTD or LTP (Bacci et al., 2004; Chavez et al., 2010, 2014; Gibson
et al., 2008; Marinelli et al., 2008, 2009), or at autapses (synaptic con­
tacts of a neuron’s axon onto its own dendrite or soma, Yin et al., 2018),
in a form of autaptic LTD (Kellogg et al., 2009). Conversely, eCBs might
also be released from presynaptic sites to act at presynaptic CB1Rs and
induce a presynaptic only form of LTD (Khlaifia et al., 2013) or at pre­
synaptic TRPV1s to induce LTP (Bialecki et al., 2020). Further, CB1Rs
located on nearby astrocytes facilitate gliotransmission and this can
result in subsequent long-term plasticity (Gomez-Gonzalo et al., 2015).
Therefore, eCBs have the capacity to induce bidirectional long-term
plasticity via multiple pathways and at a variety of different excitatory
and inhibitory synapses throughout the brain.
eCB-plasticity can be induced by a plethora of stimulation protocols
including: afferent only with or without postsynaptic depolarisation [e.
g. theta burst stimulus (TBS; Arami et al., 2013; Zhao et al., 2015); low
or high frequency stimuli (LFS, HFS respectively; Baca et al., 2015;
Chevaleyre and Castillo, 2003; Gerdeman et al., 2002; Park et al.,
2017)], spike-timing dependent (coordinated pre-/post-synaptic firing;
Andrade-Talavera et al., 2016; Sjostrom et al., 2003), and input-timing
dependent (coordinated activity of more than one afferent input; Basu
et al., 2013) stimuli, as well as repetitive strong postsynaptic depolar­
isations (Younts et al., 2013). Thus, eCB release and subsequent induc­
tion of eCB-plasticity can occur under diverse conditions of neuronal and
network activity. In addition, agonist activation of VGCCs and
Gαq/11-coupled receptors can induce persistent eCB-plasticity (Ader­
mark and Lovinger, 2007a; Azad et al., 2004; Haj-Dahmane and Shen,
2014; Izumi and Zorumski, 2008, 2016, 2016; Martin et al., 2015).
Pinpointing the underlying mechanisms that govern eCB-plasticity
however has been challenging, in part due to the diverse signalling
conditions that favour eCB-plasticity induction, which can vary sub­
stantially depending on the microcircuit and brain region studied (see
Araque et al., 2017 for review). This is further complicated by ‘atypical’
mechanisms of eCB-signalling which include their action at pre- or
postsynaptically expressed TRPV1s or CB2Rs (Li and Kim, 2016) or their
action at non-neuronal cells such as astrocytes and microglia (reviewed
elsewhere in this issue). Here we shall concentrate on fundamental
conditions required for eCB-plasticity that depend on the retrograde
action of eCBs at CB1Rs. We shall discuss the current understanding and
highlight recent advances and potential avenues for further research in
the mechanisms that govern this form of long-term eCB-plasticity, with a
particular focus on the molecular mechanisms that occur across the
synapse within pre- and postsynaptic domains.
B.L. Winters and C.W. Vaughan
4.1. Long-term eCB-plasticity requires extended CB1R activation
A key difference between short- and long-term eCB-plasticity resides
with the duration of CB1R activation. While short-term eCB plasticity is
transient and requires CB1R activity on the duration of seconds, long-
term eCB-plasticity typically requires more prolonged CB1R activation
(Chevaleyre and Castillo, 2003; Ronesi et al., 2004). Importantly, this
does not refer to the induction protocol, which are often brief high/low
frequency or spike-timing stimuli (see above). Instead, if CB1R antago­
nists are applied up to 5 min after induction, this can significantly
diminish the level of eCB-plasticity (Chevaleyre and Castillo, 2003;
Ronesi et al., 2004), suggesting CB1R activity is required to persist
beyond the duration of the induction protocol. It should be noted
however, while prolonged eCB-activation of CB1Rs is necessary for the
induction of plasticity, CB1R activity plays no role in plasticity mainte­
nance, since antagonists applied >10 min after plasticity induction have
no effect on long-term plasticity expression, which has been reported at
numerous synapses (Adermark and Lovinger, 2007a, b; Adermark et al.,
2009; Andrade-Talavera et al., 2016; Chevaleyre and Castillo, 2003;
Ronesi et al., 2004; Sjostrom et al., 2003).
Several mechanisms have the potential to underlie sustained CB1R
activation, which loosely fall into two categories: (1) increasing overall
levels of the endogenous agonist (e.g. enhanced eCB synthesis/release,
reduced eCB metabolism) or (2) enhancing the receptor (CB1R), which
includes the more controversial ideas of endosomal CB1R signalling or
an endogenous allosteric modulator or binding protein that may alter
CB1R activity.
4.1.1. Mechanisms that promote enhanced eCB synthesis and/or release for
long-term eCB-plasticity
Like short-term eCB-plasticity, a key determinant of persistent eCB-
plasticity is the ability to induce ‘on-demand’ eCB synthesis and
release. Given the prerequisite for prolonged CB1R activation (minutes
not seconds), this indicates a requirement for higher eCB-concentrations
acting at the synapse and increased demands for eCB-synthesis and
release. Indeed, manipulations that would be expected to reduce eCB
levels such as increasing FAAH/MAGL expression or knockdown of key
synthesis enzymes such as DAGLα (i.e. for 2-AG synthesis) can prevent
eCB-plasticity, whilst inhibiting or genetic deletion of FAAH/MAGL can
promote eCB-plasticity induction (Azad et al., 2004; Friend et al., 2019;
Pan et al., 2011; Schurman et al., 2019; Wang et al., 2016; Zimmermann
et al., 2019).
Since multiple pathways govern eCB-synthesis, it is possible a
mechanism divide exists between short- and long-term eCB-plasticity.
However, while early studies indicated this might be the case at single
synapses (e.g. Chevaleyre and Castillo, 2003; Edwards et al., 2006),
there is no consistency across synapses. Instead, eCB-synthesis follows
the canonical pathways described above, with the relative calcium de­
pendency (i.e. calcium dependent, calcium assisted or calcium inde­
pendent) varying depending on the stimulus or brain region studied,
rather than being a defining feature of eCB-plasticity duration (see
section 3.2; also reviewed in Hashimotodani et al., 2007a). This con­
trasts from postsynaptically expressed forms of synaptic plasticity in
which the duration and concentration of the Ca2+ signal often defines
the direction of plasticity (reviewed in Evans and Blackwell, 2015).
Interesting however, the relative contribution of the two main eCBs,
2-AG and AEA, in short-versus long-term plasticity differs at some syn­
apses. For example, in the hippocampus, 2-AG has been implicated in
the induction of DSE, DSI, LTD and LTP (Chevaleyre and Castillo, 2003;
Hashimotodani et al., 2013; Pan et al., 2011; Straiker et al., 2009),
whilst AEA appears to tonically regulate hippocampal activity (Zim­
mermann et al., 2019). Conversely at cortico-striatal synapses, AEA has
been implicated in LTD and LTP (Ade and Lovinger, 2007; Adermark
and Lovinger, 2009; Mathur et al., 2013; Ronesi et al., 2004), but 2-AG is
thought to govern short-term plasticity at this synapse (Shonesy et al.,
2018; Tanimura et al., 2010; Uchigashima et al., 2007) and it may also
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Neuropharmacology 197 (2021) 108736
have a role in the tonic control of excitatory inputs since genetic deletion
of DAGLα increases glutamate drive, particularly to direct pathway
projection neurons (Shonesy et al., 2018). Therefore, while both eCBs
can act to induce long-term plasticity, there are distinct regional dif­
ferences that favour one or other of the main eCBs for specific roles.
4.1.1.1. A role for Ca2+- and GPCR-dependent signalling and their syn­
ergistic interaction in eCB-plasticity. Since differential mechanisms of
eCB-synthesis cannot account for the enhanced duration of CB1R acti­
vation required for eCB-plasticity, it is possible some other signal may
act in conjunction with those canonically associated with short-term
plasticity (i.e. Gαq/11-coupled signalling and VGCCs) to promote suffi­
cient eCB-synthesis for sustained CB1R activation. Alternatively, the
high degree of synergy between these two main stimuli can substantially
increase eCB-synthesis/release (see section 3.1.3), suggesting eCB-
plasticity might result from the synergistic interaction of Gαq/11-
dependent signalling and Ca2+-dependent processes downstream of
postsynaptic Gαq/11-coupled receptors and L-type VGCCs. Indeed, this
has been demonstrated at synapses where DSI/DSE and eCB-LTD are
dependent on different eCB-synthesis pathways, whereby induction of
DSI/DSE can either enhance the magnitude of plasticity or reduce the
threshold for plasticity induction (Carlson et al., 2002; Chevaleyre and
Castillo, 2003; Edwards et al., 2008). Further, multiple studies found
activity-induced eCB-plasticity to be dependent on both Gαq/11 and
VGCCs. Interestingly, it has been suggested that PLCβ acts as a coinci­
dence detector due to its Ca2+ dependence, which is required for full
catalytic function and its simultaneous activation by Gαq/11-receptors, of
which PLC is the main effector (Bender et al., 2006; Fino et al., 2010;
Nevian and Sakmann, 2006). Thus, PLCβ might be key to mediating the
synergistic interaction between VGCC and Gαq/11-dependent processes
and promoting eCB-synthesis sufficient for inducing eCB-plasticity.
Importantly however, parallel activation of Gαq/11 and VGCCs is not
always a requirement for eCB-plasticity since numerous instances have
been reported in which eCB-plasticity is either VGCC or G-protein in­
dependent. In these cases, alternative signalling cascades that substitute
for one or other of the eCB-synthesis pathways have been implicated.
Indeed, multiple candidates that either directly alter intracellular cal­
cium (e.g. NMDARs, Djurisic et al., 2019; calcium permeable AMPARs,
Manz et al., 2020; Soler-Llavina and Sabatini, 2006; or increased release
of Ca2+ from intracellular stores, Bender et al., 2006; Fino et al., 2010),
or feed into the downstream signalling cascades that upregulate
PLC/DAGLα, PLC/PLD/Abdh4 to promote 2AG or AEA synthesis
respectively (e.g. BDNF/TrKB, Gangarossa et al., 2020; Lemtiri-Chlieh
and Levine, 2010; Pan et al., 2019; Zhao and Levine, 2014; see also
Hashimotodani et al., 2007a for review), have been shown to play a role
in eCB-plasticity. In particular, NMDARs have been shown to be a
requirement for eCB-plasticity at several synapses (Arami et al., 2013;
Djurisic et al., 2019; Joo et al., 2019; Liu et al., 2013; Song et al., 2018),
although this differs depending on the synapse studied and the mecha­
nism of induction (Andrade-Talavera et al., 2016; Bender et al., 2006;
Haj-Dahmane and Shen, 2010; Huang et al., 2008; Penasco et al., 2019).
Interestingly, a recent study has implicated the paired
immunoglobulin-like receptor B (PirB) as a downstream target of
NMDAR-dependent signalling that is required for postsynaptic
eCB-synthesis and/or release (Djurisic et al., 2019). Although typically
associated with immune cell function, PirBs are also expressed in neu­
rons and appear to play a role in governing dendritic spine dynamics and
structural plasticity (Bochner et al., 2014; Djurisic et al., 2013; Vidal
et al., 2016). At CA3-CA1 hippocampal synapses, eCB-LTD was impaired
in PirB− /- mice while LTP was facilitated, an imbalance that could not be
attributed to impairments in mGluR or CB1R activity (Djurisic et al.,
2019). It was suggested that PirB forms part of a negative feedback
system that limits the release of neurotransmitter by supporting eCB
retrograde signalling via an unknown mechanism. Further, since genetic
deletion or acute interference (using a recombinant ‘decoy’ receptor) of
B.L. Winters and C.W. Vaughan
PirB results in increased spine density and an increase in functional
glutamatergic synapses (Bochner et al., 2014; Djurisic et al., 2013; Vidal
et al., 2016), this NMDAR/PirB/eCB link may be essential for normal
homeostatic control of LTP and aberrant excitation. While this illustrates
the key role eCBs play in homeostatic control of excitation, further
research is required to pinpoint the mechanism in which PirB might be
acting to support eCB-synthesis or release.
In addition to directly affecting Gαq/11 or Ca2+ cascades, alterations
to the function of key initiators (e.g. mGluRs, VGCCs, NMDARs) that
interrupt or enhance eCB-synthesis would also be expected to alter eCB-
plasticity induction. Indeed, a recent study implicates changes in
NMDAR function can affect eCB signalling (Song et al., 2018). More
specifically, Song et al. found that RGS9-2− /− mice displayed reduced
NMDAR currents and impaired retrograde eCB-signalling resulting in an
increase in quantal neurotransmitter release from excitatory inputs
exclusively to striatal dopamine D2R expressing medium spiny neurons,
which are known to form part of the basal ganglia indirect pathway
(iMSN; (Song et al., 2018). RGS9-2 is a regulator of G-protein signalling
protein (RGS) that accelerates intrinsic GTPase activity to inactivate
G-protein signalling and has been associated with several Gαi/o-coupled
receptors including: mu-opioid receptors and D2Rs (Cabrera-Vera et al.,
2004; Psifogeorgou et al., 2011). It was suggested RGS9-2 decreases
Gαi/o-dependent signalling, which would increase cAMP/PKA activity
(since Gαi/o-control of adenylyl cyclase is reduced) and increase
PKA-phosphorylation of NMDARs, which is known to increase NMDAR
function and presumably promote eCB-synthesis (Skeberdis et al., 2006;
Song et al., 2018). However, the role of postsynaptic cAMP and PKA
with regards to eCB-plasticity is not straightforward. For example, ge­
netic deletion of adenylyl cyclase 5 (AC5), an isoform enriched in striatal
MSNs, was shown to impair eCB-LTD but via a mechanism of occlusion
since postsynaptic loading of cAMP impaired eCB-LTD in wildtype mice
but induced LTP in AC5− /− mice (Kheirbek et al., 2009). Indeed, while
low intracellular cAMP levels are permissive for eCB-LTD, higher levels
appear to promote NMDAR-dependent LTP at this synapse (Augustin
et al., 2014). The mechanism described in this instance was attributed to
PKA-mediated phosphorylation and activation of RGS4, another RGS
protein that inhibits the activity of Gαq/11-coupled receptors, including
mGluRs (Lerner and Kreitzer, 2012). In fact, this mechanism has been
implicated in D2R/mGluR/VGCC-dependent eCB-LTD at cortico-striatal
synapses, in which activation of Gαi/o-coupled D2Rs is a requirement for
eCB-LTD (Augustin et al., 2014; Kheirbek et al., 2009; Kreitzer and
Malenka, 2005; Lerner and Kreitzer, 2012; Pawlak and Kerr, 2008; Yin
and Lovinger, 2006), whilst activation of Gαs-coupled adenosine A2
receptors (which increases cAMP/PKA) impairs eCB-LTD (Tozzi et al.,
2011). The reason for this discrepancy in function for postsynaptic
cAMP/PKA signalling is unclear, although it may suggest a degree of
compartmentalisation that segregates cAMP/PKA control of NMDARs
with that of mGluRs, perhaps via differential activation of the various
RGS proteins or dynamic regulation of the postsynaptic density (see
below). It should also be noted, the precise cellular locus of D2Rs
required for eCB-LTD is under debate and recent evidence suggests D2Rs
that are expressed on cholinergic interneurons (which reduce acetyl­
choline release and prevent M1AChR-inhibition of L-type VGCCs), play a
more significant role in governing eCB-LTD at corticostriatal synapses
than those expressed postsynaptically on iMSNs (Augustin et al., 2018;
Wang et al., 2006). However, since much of this work has been con­
ducted at striatal synapses, it is not clear whether these mechanisms are
specific to this region. In this regard, it is interesting to note PKA has
recently been shown to directly phosphorylate DAGLα which enhances
DAGLα activity and increases the magnitude of DSE in striatal D1R
expressing MSNs, which form part of the basal ganglia direct pathway
(dMSN; Shonesy et al., 2020). Similarly, eCB-iLTD at inhibitory inputs to
principal neurons of the basolateral amygdala was found to be depen­
dent on mGluR1 and PKA activity, but independent of PLC and DAGLα
activity (Azad et al., 2004). Conversely, eCB-iLTD in the ventral
tegmental area (VTA) was impaired when an agonist of Epac (exchange
9
Neuropharmacology 197 (2021) 108736
protein directly activated by cAMP) was intracellularly loaded into
dopaminergic VTA neurons (Tong et al., 2017). Clearly there is a com­
plex interplay between the downstream signalling of Gαq/11-, Gαi/o-,
Gαs-coupled receptors which can significantly alter eCB-synthesis and
release required for eCB-plasticity. The extent to which likely varies
depending on the microcircuit studied and the degree of integration
with other neurotransmitter systems that signal within a dynamic
network.
4.1.1.2. A role for an ‘endocannabinoid signalosome’ and other post­
synaptic molecular complexes in eCB-plasticity?. Beyond enhancing syn­
ergy between the two eCB-synthesis pathways, the molecular
mechanisms that underlie enhanced eCB synthesis at GABAergic syn­
apses remain poorly understood. More progress has been made at glu­
tamatergic synapses, where there is good evidence to suggest key
elements required for eCB-synthesis including mGluRs, VGCCs, PLCβ,
DAGLα exist in a ‘signalosome’ which is held in close proximity to the
perisynapse in dendritic spines by longer coiled-coiled-forms of homer
(homer-1b & homer-2), key scaffolding proteins known to directly or
indirectly interact with L-type VGCCs, mGluR5 and DAGLα (Brakeman
et al., 1997; Jung et al., 2007, 2012; Olson et al., 2005; Piomelli, 2014;
Zhang et al., 2005). Although this ‘eCB-signalosome’ has so far only
been implicated in 2-AG signalling, the supramolecular complex may
provide a focal point for eCB generation dedicated to retrograde trans­
mission that is separate from functions such as eicosanoid production or
phospholipid remodelling (see in Jung et al., 2012; Piomelli, 2014). It
may also facilitate synergy between VGCC-independent Ca2+ signalling
and Gαq/11 signalling since homer interacts with the Shank family of
scaffolding proteins, which provides a molecular link with NMDARs via
PSD-95 (Bertaso et al., 2010; Tu et al., 1999, although see below). In this
regard, an interesting regulatory mechanism was reported, which in­
volves BDNF/TrKB-dependent increases in the expression of the imme­
diate early gene homer1a (Roloff et al., 2010). Homer1a is a truncated
isoform of homer1 that lacks the coiled-coiled C-terminus preventing
homer multimerization but the N-terminal EVH1-domain, which medi­
ates interactions with mGluRs and shank, is preserved (Ango et al.,
2001). Therefore, homer1a acts in a dominant negative capacity to
disassemble crosslinked complexes and prevent mGluRs and possibly
other members of the eCB-signalosome from interacting with longer
isoforms of homer (Ango et al., 2001; Clifton et al., 2019; Ronesi et al.,
2012). Indeed, BDNF was shown to inhibit mGluR-dependent short-term
eCB-plasticity at excitatory hippocampal synapses due to increases in
homer1a expression (Roloff et al., 2010) and it was previously reported
that BDNF impairs eCB-LTD at excitatory synapses in the visual cortex of
juvenile mice (Huang et al., 2008). However, it is not clear whether
these results reflect homer1a interference with the assembly of
eCB-synthesis machinery or the resulting constitutive activity of mGluRs
(a widely reported effect of homer1a, Ango et al., 2001; Hu et al., 2010;
Ronesi et al., 2012), which would occlude eCB-signalling and has been
implicated in mouse models of fragile X syndrome (Aloisi et al., 2017;
Guo et al., 2016; Jung et al., 2012; Ronesi et al., 2012; Tang and Alger,
2015). Moreover, the role of BDNF in eCB-plasticity may be bidirec­
tional since several other reports indicate BDNF signalling acts to
facilitate eCB-synthesis in various brain regions (Gangarossa et al.,
2020; Lemtiri-Chlieh and Levine, 2010; Maison et al., 2009; Pan et al.,
2019; Zhao et al., 2015; Zhong et al., 2015), which likely involves
cross-talk of TrKB-dependent signalling cascades to increase the activity
of PLCβ or DAGLα (Pan et al., 2019; Zhao et al., 2015; Zhong et al., 2015)
or prolonging intracellular calcium transients (Gangarossa et al., 2020).
Another molecular scaffold that controls mGluR surface expression
and sets a threshold for mGluR activation to trigger eCB-plasticity in
striatal medium spiny neurons has been described involving SAP90/
PSD-95 associated proteins (SAPAP; also known as GKAP, Chen et al.,
2011). SAPAPs are a family of scaffolding proteins that bind to PSD-95 in
a phosphorylation-dependent manner and to Shank via a PDZ domain
B.L. Winters and C.W. Vaughan
(Zeng et al., 2016; Zhu et al., 2017). PSD-95/SAPAP/Shank, together
with Homer1-3, form a core molecular complex of the postsynaptic
density that links ionotropic glutamate receptors (i.e. AMPAR and
NMDARs) with mGluRs (reviewed in Kim and Sheng, 2004; Ting et al.,
2012). Intriguingly in SAPAP3 knockout mice, the threshold for
mGluR-induced (CB1R-dependent) depression was considerably
reduced, suggesting SAPAP3 acts to limit eCB-plasticity induction by
somehow limiting the surface availability of mGluRs (Chen et al., 2011).
It is possible activity-dependent regulation of the interaction between
SAPAP and PSD-95 may play a role in this gating of eCB-plasticity,
although at present the evidence supporting this is incomplete. Firstly,
it is known that CaMKIIα and β directly phosphorylate SAPAP at
different N-terminal residues which can either induce poly­
ubiquitination and presumably degradation of SAPAP or increase SAPAP
integration within the postsynaptic density (Shin et al., 2012). Secondly,
phosphorylation within an N-terminal ‘GK-binding repeat’-motif
(14-amino acid repeats) that corresponds to the site targeted by CaMKII
and increased SAPAP integration with the postsynaptic density, facili­
tated SAPAP binding to PSD-95 (Shin et al., 2012; Zhu et al., 2017).
Thirdly, aberrant CaMKII activity associated with stress has been shown
to impair eCB-LTD in the lateral habenula (Park et al., 2017) and it
negatively modulates DSE in the striatum (Shonesy et al., 2013),
although the latter was attributed to CaMKII directly phosphorylating
DAGLα and inhibiting its activity (Shonesy et al., 2013). Together, these
findings indicate the molecular scaffolding that links mGluRs and
NMDARs hinders eCB-signalling, which appears to contrast with the
findings reported above. It is possible that while long-homer might act as
a molecular ‘dock’ for eCB-synthesis machinery, the additional inter­
action with SAPAP/PSD95/NMDAR might restrict and compartmen­
talise the diffusion of rate-limiting signals such as Ca2+. It is tempting to
speculate that the gating of sufficient eCB-synthesis for eCB-plasticity is
dynamically regulated via activity-dependent changes in the molecular
complexes that constitute the postsynaptic density, which may alter the
molecular links between Ca2+ and Gαq/11-dependent pathways. How­
ever, it is important to note that this potential link can only pertain to
glutamatergic synapses since the complex postsynaptic architecture
containing PSD-95 are absent at GABAergic synapses (see Sheng and
Kim, 2011 for review). Further work is required to fully elucidate the
dynamics that regulate the ‘eCB-signalosome’ and other molecular un­
derpinnings that promote eCB synthesis and plasticity in this regard.
4.1.1.3. Does eCB-plasticity require a regulated eCB-release mechanism?.
It is possible sufficient eCB-release to induce eCB-plasticity requires a
regulated release mechanism such as through a membrane transporter
(Fowler, 2013; Nicolussi and Gertsch, 2015). Since eCBs are lipophilic
signalling molecules that can readily diffuse through lipid membranes,
facilitated release is not strictly required. However, at striatal and so­
matosensory cortical synapses, facilitated eCB release through the pu­
tative AEA membrane transporter (AMT) was shown to be a requirement
for plasticity induction (Adermark and Lovinger, 2007b; Adermark
et al., 2009; Maglio et al., 2018; Ronesi et al., 2004). Interestingly, when
AEA was delivered postsynaptically to striatal MSNs to bypass the need
for eCB synthesis, release of this eCB was dependent on the strength of
afferent activation (Adermark and Lovinger, 2007b). Whilst gluta­
matergic inputs required a stronger pre-synaptic stimulus; at GABAergic
synapses, spontaneous activity was sufficient to induce eCB-LTD but the
magnitude of depression could be enhanced by extracellular stimuli
(Adermark and Lovinger, 2007b). These findings indicate eCB release
depends on sufficient pre-synaptic activity, which might upregulate the
activity of a postsynaptically expressed transporter via an unknown
mechanism to facilitate eCB release (Adermark and Lovinger, 2007b;
Adermark et al., 2009; Ronesi et al., 2004).
It should be noted however, the involvement of AMT is controversial.
While activity and pharmacological assays support the existence of an
eCB transporter (Chicca et al., 2012; Maglio et al., 2018; Moore et al.,
10
Neuropharmacology 197 (2021) 108736
2005; Ronesi et al., 2004), to date no single candidate has been identi­
fied (reviewed in Fowler, 2013; Nicolussi and Gertsch, 2015), although
several targets have been implicated, including: FAAH-like AEA trans­
porter; (FLAT; Fu et al., 2011), fatty acid binding proteins (FABP;
Haj-Dahmane et al., 2018; Kaczocha et al., 2009); and most recently,
Pannexin-1 (an ion/metabolite channel; Bialecki et al., 2020). Further,
the precise role of these candidates is unclear, with evidence indicating
they primarily act as reuptake transporters to promote the clearance and
catabolism of AEA (Bialecki et al., 2020; Fu et al., 2011; Kaczocha et al.,
2009). In the case of FLAT, it was suggested this protein may also act as a
means of translocating AEA across the synaptic cleft due to its weak
membrane binding properties and bidirectional transport of AEA into
and out of HEK293 cells (Fu et al., 2011). Similarly, a putative endo­
cannabinoid membrane transporter (EMT) was identified in U937
human monocytes/macrophages that could bidirectionally transport
both AEA and 2-AG, as well as other structurally related eicosanoid eCBs
down their concentration gradients (Chicca et al., 2012). Further, FABP5
was recently implicated in controlling the retrograde transport of 2-AG,
in which pharmacological inhibition or genetic deletion of FAB5 could
impair eCB-LTD and eCB-dependent tonic control of glutamatergic in­
puts to dorsal raphe neurons (Haj-Dahmane et al., 2018). In this regard,
it is interesting to note that a recent study implicates a novel mechanism
in which 2-AG is contained within non-synaptic extracellular vesicles
and is released via a process involving vesicle fusion (Nakamura et al.,
2019). FABP5 was found to colocalise with these extracellular vesicles
and although not directly shown, it was suggested 2-AG binding to
FABP5 may facilitate its release to the extracellular space (Nakamura
et al., 2019). It is possible one or all these candidates may facilitate
either eCB release or the retrograde transport of eCBs across the synaptic
cleft. However, direct observations of eCB transporters within a physi­
ological context are sparse, with FABP5 being the first to be linked to
long-term eCB-plasticity. Further complexity is given by the poor spec­
ificity of the transport inhibitors, which are known to have several
off-target effects including activating TRPV1 (Zygmunt et al., 2000),
sodium channels (Kelley and Thayer, 2004), calcium channels (Alptekin
et al., 2010), CB2Rs (Sagar et al., 2010) and inhibiting FAAH/MAGL
(Vandevoorde and Fowler, 2005) (also reviewed in Nicolussi and
Gertsch, 2015). It therefore remains to be seen whether a transporter is a
central requirement for enhanced eCB-release to sufficiently sustain
CB1R activation for long-term eCB-plasticity.
4.1.1.4. Activity-dependent regulation of eCB-breakdown?. It is possible
downregulation of the respective degrative enzymes MAGL and FAAH
that hydrolyse 2-AG or AEA (respectively) may underlie sustained CB1R
activity required for plasticity induction, since this would be expected to
extend the lifetime of the eCB signal. Indeed, as previously mentioned,
inhibitors of either enzyme can either reduce the threshold for LTD/LTP
or increase the magnitude of plasticity at numerous synapses throughout
the brain (see section 4.1.1). Similarly, inhibitors of the more recently
identified ABHD6, which hydrolyses 2-AG at postsynaptic sites, was
shown to facilitate LTD induction in the prefrontal cortex to otherwise
subthreshold stimuli (Marrs et al., 2010). Endogenous regulation of
MAGL, FAAH and ABHD6 activity is not well defined, but likely involves
changes in overall expression, rather than post-translational modifica­
tions. In this regard, ketamine (a known modifier of synaptic plasticity;
Luo et al., 2020; Maren et al., 1991; Salami et al., 2000; Stringer and
Guyenet, 1983), was shown to increase 2-AG levels in the dorsal stria­
tum by increasing the expression of PR domain protein 5 (PRDM5),
which functions as a transcriptional repressor of MAGL (Xu et al., 2020).
Similarly, a link between presynaptic BDNF signalling, reduced MAGL
expression but increased CB1R expression in cultured cerebellar granule
neurons has been reported (Maison et al., 2009). Although as previously
stated, the interaction between BDNF and eCB signalling is complex,
since BDNF also acts at postsynaptic sites to facilitate or inhibit
eCB-plasticity (see section 4.1.1). Conversely, the growth factor
B.L. Winters and C.W. Vaughan
neuregulin-1 was shown to enhance the degradation of 2-AG by acting at
ErbB receptor tyrosine kinases to increase the expression of MAGL,
which reduced the magnitude of iLTD at hippocampal synapses (Du
et al., 2013). Similarly, FAAH expression is known to be upregulated by
oestrogen (Grimaldi et al., 2012) and progesterone (Maccarrone et al.,
2003) signalling although a link between this and eCB-plasticity has yet
to be made. Indeed, while these studies demonstrate the expression and
putative activity of MAGL/FAAH can be regulated, it is not clear
whether this a requirement for long-term eCB plasticity. Nevertheless,
given the plethora of evidence illustrating plasticity is facilitated when
these enzymes are pharmacologically inhibited, any process that results
in a reduction in their activity or expression would be expected to pro­
mote eCB-plasticity.
4.1.2. Possible mechanisms to enhance CB1R signalling
4.1.2.1. CB1R signalling from intracellular compartments?. An under­
studied mechanism of enhanced CB1R signalling in relation to long-term
eCB plasticity is the possibility of CB1R signalling from intracellular
compartments such as endosomes or mitochondria. As with the majority
of GPCRs, agonist binding to CB1Rs recruits β-arrestin and promotes
clathrin-dependent receptor endocytosis (Gainetdinov et al., 2004;
Magalhaes et al., 2012). Traditionally, this process is viewed as a
mechanism of receptor desensitisation and/or inactivation whereby
CB1Rs are excluded from synapses (Mikasova et al., 2008), removed
from the cell surface and may be targeted to either early or late endo­
somes for recycling or lysosomal degradation (respectively; Gainetdinov
et al., 2004; Magalhaes et al., 2012). It is also a major caveat to the idea
that eCB-plasticity requires prolonged CB1R activity since these inacti­
vation/desensitisation mechanisms would be expected to be engaged
following eCB binding. Indeed, exogenous CB1R agonists such as THC
have been shown to desensitise CB1Rs and impair eCB-LTD (Neuhofer
et al., 2020). Similarly, chronic inhibition of MAGL or genetic deletion,
which produces an excess of 2AG, was shown to downregulate CB1Rs in
numerous brain regions and impair eCB-plasticity (Imperatore et al.,
2015; Schlosburg et al., 2010). However, it is not clear whether condi­
tions that promote eCB-plasticity also promote CB1Rs desensitisation or
whether ‘prolonged’ activation represents a sustained eCB signal that
engages a greater number of CB1Rs over a larger time-space period (e.g.
extrasynaptic CB1Rs). As an interesting alternative, there is good evi­
dence to indicate CB1Rs are capable of signalling from endosomal lo­
cations (Brailoiu et al., 2011; Rozenfeld and Devi, 2008; see also Jong
et al., 2018 for a review on intracellular GPCRs in synaptic plasticity).
Indeed, CB1Rs were found to be associated with Gαi/o in Rab7 positive
late-endosomal fractions and agonists such as WIN55,212–2 can induce
ERK1/2 phosphorylation (and activation) in the presence of membrane
impermeable CB1R antagonists (Rozenfeld and Devi, 2008). Further,
given CB1Rs are enriched within the endosomal system, while plasma
membrane CB1Rs comprises ~20 % of total CB1Rs (Leterrier et al., 2006;
Rozenfeld and Devi, 2008), it is possible endosomal signalling of CB1Rs
is a common feature of their activity. Aside from endosomes, CB1Rs are
also expressed at mitochondrial membranes (so called mtCB1Rs) and
have been shown to reduce cellular respiration and energy production in
neuronal mitochondria (Benard et al., 2012). Remarkably, these
mtCB1Rs we found to contribute to DSI (Benard et al., 2012) and a
longer form of agonist-induced depression of excitatory synaptic trans­
mission in hippocampal slices, which was linked to acute
cannabinoid-induced memory impairments in novel object recognition
(Hebert-Chatelain et al., 2016). It is therefore possible mtCB1Rs
contribute towards the induction of long-term eCB-plasticity. This is
particularly compelling given mitochondria are known to support the
energy demand of highly active synapses (Sheng, 2014) and recent ev­
idence suggests mitochondria may be dynamically regulated to affect
synaptic strength (Cserep et al., 2018; Sheng, 2014). In this regard, it
would be tempting to propose eCBs may be required to activate both
11
Neuropharmacology 197 (2021) 108736
membrane and subcellularly expressed CB1Rs for plasticity induction.
Given the lipophilicity of eCBs and the likelihood of a diffusion delay
between membrane expressed receptors and those expressed within
intracellular compartments, it is conceivable the extended activation of
CB1Rs required for plasticity induction reflects activation of these two
different pools of receptors. Further research in the area is required to
fully elucidate the functional role of CB1Rs signalling from intracellular
compartments.
4.1.2.2. Activity-dependent changes in the interaction with binding partners
or other modifiers may alter CB1R affinity or efficacy?. Other intriguing
possibilities for modifying CB1R activity are: direct or indirect post-
translational modification (Madeo et al., 2016), altered interactions
with binding partners (Niehaus et al., 2007) or endogenous allosteric
modulators (Lu et al., 2019; Pamplona et al., 2012; Straiker et al., 2015),
each of which might have the capacity to alter the affinity or efficacy of
eCBs at CB1Rs or alter CB1R interaction with its downstream effectors.
Indeed, lipoxin A4, an oxygenated derivative of arachidonic acid and a
known anti-inflammatory mediator, was shown to bind to and enhance
CB1R signalling in assays of cAMP production and activation of inwardly
rectifying K+ channels (Pamplona et al., 2012). Of particular note,
knock-out mice that were deficient for the PTEN-induced putative ki­
nase 1 (PINK1− /− ), were shown to have impaired binding ability of CB1R
agonists, which could be restored following D2R activation (Madeo
et al., 2016). Although the mechanism is unclear, this could indicate a
role for PINK1 to indirectly promote eCB-CB1R interaction, perhaps
through modification of the interaction of CB1Rs with binding proteins
such as CRIP1a/b, which are known to limit CB1R activity (Booth et al.,
2019; Madeo et al., 2016; Niehaus et al., 2007). However, to our
knowledge, no reports have found a link between any of these possible
modifications to CB1R function and long-term eCB-plasticity. In fact, in
the case of DSE, lipoxin A4 was found to have no effect on the magnitude
of DSE in cultured hippocampal neurons (Straiker et al., 2015). Never­
theless, these may provide compelling avenues for further research.
4.2. eCB-plasticity depends on highly regulated spatiotemporal
coordination of pre- and postsynaptic activity
4.2.1. CB1R activation provides a temporal window for eCB-plasticity
induction
Although CB1R activation is necessary for long-term eCB-plasticity
induction, a plethora of evidence indicates it is not sufficient and there is
a clear presynaptic requirement that has not been well defined. Indeed,
multiple reports indicate activation of CB1Rs either directly (agonist) or
indirectly (upregulation of eCB synthesis) in the absence of adequate
afferent activity fails to produce long-term plasticity (Adermark and
Lovinger, 2007a, b; Edwards et al., 2006; Heifets et al., 2008; Martin
et al., 2015; Ronesi et al., 2004; Singla et al., 2007; Sjostrom et al.,
2003). It has been suggested that presynaptic activity may act as a
cofactor for plasticity induction, which is independent of eCB release
and CB1R activation (Heifets and Castillo, 2009; Heifets et al., 2008).
This was demonstrated in CA1 pyramidal neurons where iLTD, which
was inhibited when spontaneous activity was reduced using low dose
TTX, could be rescued by an afferent stimulus delivered immediately
after the TBS induction protocol (Heifets et al., 2008). Further, paired
recordings between hippocampal interneurons and pyramidal neurons
showed DHPG-induced iLTD, which would be expected to induce the
release of eCBs, was abolished if the presynaptic interneuron was held
silent (Heifets et al., 2008). Yet evidence from striatal synapses indicates
adequate presynaptic activity is required to facilitate postsynaptic eCB
release, which is independent of eCB synthesis (Adermark and Lovinger,
2007a; Adermark et al., 2009; Ronesi et al., 2004; although see discus­
sion above on eCB transporters). Therefore, it is not clear whether pre­
synaptic activity is required to enhance postsynaptic eCB release or to
facilitate an unknown presynaptic mechanism that acts in conjunction
B.L. Winters and C.W. Vaughan
with presynaptically expressed CB1Rs to persistently reduce the proba­
bility of neurotransmitter release. Given the nature of eCB-plasticity (i.e.
postsynaptically induced, but presynaptically expressed), it is likely the
coordinated activity of both pre- and postsynaptic activity is required.
Indeed, all forms of associative plasticity (including eCB-plasticity)
require some form of coordinated and temporally correlated pre-/­
post-synaptic activity, the order of which determines the direction of
plasticity as defined by Hebbian or anti-Hebbian learning rules (Feld­
man, 2012). Hebbian plasticity describes when synaptic strengthening
(LTP) results from activity in which presynaptic inputs lead or are syn­
chronous with postsynaptic spikes (pre-post), while synaptic weakening
(LTD) results from postsynaptic spikes preceding presynaptic input
(post-pre). In contrast, anti-Hebbian plasticity reflects the opposite of
these conditions (LTP: post-pre; LTD: pre-post). It is interesting to note
eCBs have been implicated in both Hebbian and anti-Hebbian forms of
plasticity (Andrade-Talavera et al., 2016; Bender et al., 2006; Cui et al.,
2015, 2018; Fino et al., 2010; Tzounopoulos et al., 2007; Zhao and
Tzounopoulos, 2011). Further, the intensity of afferent activity used to
induce eCB-plasticity can vary widely even within the same synapses,
but it is required within a limited time frame (Martin et al., 2015; Singla
et al., 2007; Sjostrom et al., 2003). For example, when endogenous
acetylcholine release was evoked optogenetically to act a
Gαq/11-coupled M1AChRs, eCB-LTD of excitatory inputs to prelimbic
cortical neurons was only induced when the light stimulus was delivered
in conjunction with an appropriately timed extracellular afferent
(Martin et al., 2015). Therefore, it is not the intensity of presynaptic
activity per se, rather the duration of eCB-CB1R activation provides a
window in which temporally appropriate presynaptic activity is
required to induce long-term eCB-plasticity (Martin et al., 2015; Sjos­
trom et al., 2003). Although there appears to be no single rule for
afferent activity or the duration of CB1R action, variations in the pat­
terns, timing and order of pre- and/or post-synaptic stimulation can
drastically alter expression of eCB-plasticity; indeed, this temporal
requirement has been widely reported at several synapses (Adermark
and Lovinger, 2009; Adermark et al., 2009; Cui et al., 2016; Heifets
et al., 2008; Martin et al., 2015; Singla et al., 2007; Sjostrom et al.,
2003).
The degree of pre-/postsynaptic coordination required will likely
depend on several synaptic attributes. Firstly, as previously described,
patterns of activity that upregulate both eCB-synthesis pathways would
be expected to generate higher eCB concentrations (see sections 3.1.3 &
4.1.1; also reviewed in Hashimotodani et al., 2007a). As a result, this
may either overcome enzymatic degradation, thus increasing the chance
of eCBs interacting with their receptors or eCBs may diffuse greater
distances from their release site to engage CB1Rs expressed extra­
synaptically. Secondly, the relative expression level of CB1Rs at axon
terminals and whether there is a receptor reserve (i.e. an excess of re­
ceptor number required for full activation of the effector) will determine
how strongly these receptors engage downstream signalling following
activation. This is particularly relevant to the differences between
eCB-plasticity at GABAergic and glutamatergic synapses, arising from
their relative expression of CB1Rs (see sections 2.1 & 2.2). While
eCB-plasticity is readily expressed at glutamatergic synapses, induction
protocols often require stronger stimuli or more coordinated patterns of
pre-/post-synaptic activity or activation of multiple inputs (Adermark
and Lovinger, 2007b, 2009, 2009; Adermark et al., 2009; Penasco et al.,
2019; Peterfi et al., 2012). Thirdly, the strength of the signal following
CB1R activation will depend on how tightly these GPCRs are coupled to
their effectors (i.e., VGCCs, Kirs and adenylyl cyclase). In this regard, it is
interesting to note that while glutamatergic terminals express fewer
CB1Rs, there is evidence to suggest they maybe more tightly coupled to
their downstream effectors (Steindel et al., 2013). At present, these
differences between glutamatergic and GABAergic CB1R expression
levels and their relative coupling with effectors are difficult to reconcile.
It has been suggested at synapses expressing high levels of CB1Rs that
exhibit lower efficiency signalling, the excess CB1Rs may be performing
12
Neuropharmacology 197 (2021) 108736
an additional role outside of their canonical receptor function. For
instance, providing a reserve pool of receptors that might facilitate rapid
eCB-signalling under certain conditions or perhaps to sequester Gαi/o
proteins from other GPCRs expressed at the same terminal (Vasquez and
Lewis, 1999; and also discussed in Busquets-Garcia et al., 2018).
4.2.2. eCB-plasticity is spatially constrained to active synapses
Another feature of long-term eCB-plasticity is that it is relatively
input specific and expressed at synapses that are highly localised to
those engaged by the site of stimulation (Chevaleyre and Castillo, 2003,
2004, 2004; Soler-Llavina and Sabatini, 2006). While precise temporal
pre-/postsynaptic coordination plays a part in this specificity, it also
concerns the degree of eCB diffusion from its release site, which provides
spatial constraints to eCB signalling. For eCBs to induce long-term
plasticity at inhibitory synapses, a degree of diffusion is expected be­
tween the site of eCB-release and inhibitory terminals. Particularly since
eCB-plasticity of inhibitory synapses is largely heterosynaptic and re­
quires non-GABAergic inputs (e.g. cholinergic, glutamatergic etc.) to
activate Gαq/11-coupled signalling and initiate eCB synthesis to act at
CB1Rs that are presumably located outside of the site of release (i.e. at
inhibitory terminals). However, whilst eCBs may travel considerable
distances (up to 100 μm) under certain conditions (Kreitzer et al., 2002),
long-term eCB-plasticity is restricted to inputs located within 10–20 μm
of the site of afferent stimulation (Chevaleyre and Castillo, 2003, 2004,
2004; Soler-Llavina and Sabatini, 2006). This suggests eCB signalling
induced by patterns of presynaptic activity, is restricted to a small region
along the somatodendritic axis. Yet, when eCB-iLTD was induced with
multiple postsynaptic depolarisations delivered at theta frequency, iLTD
was expressed at both somatic and dendritic inputs to CA1 pyramidal
neurons, indicating at actively firing neurons, eCB-plasticity might be
induced across the whole somatodendritic axis (Younts et al., 2013).
Then again, while eCB-plasticity was more globally expressed in depo­
larised neurons, there were limitations to this: (i) iLTD was specific to
the depolarised neuron, (ii) it was compartmentalised to GABAergic
inputs and (iii) postsynaptic firing was required at specific theta fre­
quencies (a network oscillation displayed during active waking (Younts
et al., 2013). Nevertheless, these findings are particularly intriguing as
they suggest a functional difference between afferent and
somatic-depolarisation induced eCB-plasticity. Highly localised
eCB-plasticity induced by patterns of afferent activity, likely plays a role
in fine tuning synaptic strength in an active network. This specificity to
active synapses has significant implications for the integration of
different inputs to overall somatic output. While eCB-signalling at
proximal dendrites might be expected to alter somatic output, given the
distance required for signal propagation to the soma, eCB-action at distal
dendrites might have less of an effect (although see Menon et al., 2013;
Nicholson et al., 2006). Instead, local signalling at distal sites might alter
the threshold of plasticity at proximal dendrites (Dudman et al., 2007).
In this regard however, the metaplastic eCB-dependent facilitation of
LTP in CA1 pyramidal neurons was restricted to pathways located
within 10 μm of one another (Younts et al., 2013). It is also interesting to
note that super-resolution imaging of hippocampal GABAergic axons,
indicates perisomatic interneurons (i.e. interneurons located close to the
CA1 pyramidal cell layer) contain a more complex active zone with a
higher number of CB1Rs and greater receptor/effector ratio compared
with dendritic interneurons (Dudok et al., 2015); although the func­
tional consequence of this has yet to be investigated. Nevertheless, the
high specificity of afferent-induced eCB-plasticity to active synapses
indicates a subtle modulatory role of eCBs over neuronal activity.
Conversely, when neurons are actively firing at frequencies such as those
used in the theta burst firing protocol, which relies on
somatic-depolarisation (Younts et al., 2013), eCBs may act to alter
synaptic inputs across the entire somatodendritic axis. In the case of CA1
pyramidal neurons, in which only inhibitory inputs are affected by
postsynaptic depolarisation-induced eCB-plasticity (Younts et al., 2013),
this could play a role in sustaining excitatory rhythms of activity that
B.L. Winters and C.W. Vaughan Neuropharmacology 197 (2021) 108736

have been associate with behaviourally relevant processes such as theta
and active waking. Indeed, in instances when eCB-signalling has become
overactivated and dysregulated, the resulting hyperexcitability has been
linked to early epileptiform activity in the hippocampus, although it
should be noted that eCB signalling at later stages supresses seizure
generation (see Sugaya and Kano, 2018 for review).
4.3. Presynaptic mechanisms underlying induction and expression of
long-term eCB-plasticity
Substantial progress has been made in understanding signal trans­
duction pathways that are upregulated following CB1Rs activation, the
consequence of which ranges from alterations in neuronal excitability to
changes in nuclear transcription/translation (see Howlett, 2005;
Howlett et al., 2002; Turu and Hunyady, 2010 for reviews). To briefly
recap, CB1Rs are canonically coupled to Gαi/o G-proteins which down­
regulate the activity of adenylyl cyclase and can also inhibit VGCCs and
activate inwardly rectifying K+ channels (Kir/GIRKs) via βγ-subunit
signalling (see section 2.1). In addition, via a mechanism that likely
involves either Gαi/o-inhibition of c-Raf (which is usually phosphory­
lated by PKA and inhibits Raf kinase/MEK) or βγ-recruitment of the
PI3K-Akt pathway, CB1Rs activate MAPK signalling pathways including
ERK and p38 (Derkinderen et al., 2001, 2003; Galve-Roperh et al., 2002;
see also Howlett, 2005 for review). Thus, CB1Rs have the capacity to
upregulate numerous downstream signalling pathways. Despite these
advances, the precise mechanisms responsible for persistent reduction in
presynaptic activity are not well characterised. This is because the study
of real time presynaptic dynamics has been problematic due to limita­
tions in available technology able to access the presynaptic bouton
(discussed below). Nevertheless, substantial evidence implicates
eCB-plasticity depends on CB1R-dependent alterations in the activity of
adenylyl cyclase and/or VGCCs, the relative contribution of which may
vary depending on the synapse studied (discussed below). In contrast, to
our knowledge, little evidence has implicated a mechanism involving

Fig. 2. CB1Rs alter active zone signalling at presynaptic terminals to persistently reduce the probability of neurotransmitter release. Schematic depicting
putative pathways in which the active zone matrix might be altered downstream of presynaptic CB1R activation. Activation of CB1Rs initiates Gαi/o to inhibit adenylyl
cyclase (AC) and downregulate cAMP/PKA dependent signalling. (1) This prevents PKA from phosphorylating RIM1α, which reduces its interaction with other active
zone matrix proteins, including Rab3 located on synaptic vesicles, an interaction that is required to prime synaptic vesicle docking. (2) Once activated, CB1Rs
somehow interact with the GTPase Rac1 to inhibit GTP binding and activation of Rac1. (3) This prevents GTP-bound Rac1 from interacting with the WAVE1 complex,
exposing the VCA region (where activated ARP 2/3 binds), and allowing WAVE1/Arp 2/3 mediated assembly of F-actin from G-actin monomers. This inhibition of
actin polymerisation likely impairs synaptic vesicle transport from reserve pools to the active zone matrix and thus reduces the availability of neurotransmitter for
release. (4) Meanwhile, downstream of Gβγ signalling, voltage gated calcium channels (VGCC) are inhibited whilst mTOR is activated likely via Gβγ upregulation of
PI3K/Akt signalling pathways. mTOR initiates the nucleation of mTORC1/mTORC2 complexes, which are involved in numerous cellular processes including local
cap-dependent protein synthesis. (5) Newly synthesised proteins include ubiquitin-proteosome-system (UPS)-related proteins, whilst WAVE1, ARP2/3 (Arpc2),
synapsin, MUNC18, SNAP-25 and other active zone proteins are ubiquitinated in functional domains, which impairs key interactions and may target the proteins for
proteosomal degradation (6). Importantly, whilst protein ubiquitination is required of eCB-iLTD expression, proteosomal degradation was not but it may promote
subsequent reduction in presynaptic bouton volume and long-term weakening of the synapse.

13
B.L. Winters and C.W. Vaughan
GIRKs, suggesting persistent CB1R-βγ activation of these channels likely
does not determine eCB-plasticity (see also in Lovinger, 2008).
4.3.1. Alterations in the presynaptic active zone matrix downstream of
CB1R activation may underlie eCB-plasticity
The reduction in neurotransmitter release associated with CB1R-
induced inhibition of presynaptic VGCCs is typically associated with
short-term depression of synaptic transmission (section 2.1). By
contrast, only a handful of studies have implicated presynaptic VGCCs as
a requirement for long-term eCB-plasticity (Huang et al., 2003; Mato
et al., 2008) and it is not clear whether this is due to persistent CB1R-βγ
effects or whether some other mechanism is at play. More progress has
been made in the understanding of Gαi/o-downregulation of adenylyl
cyclase activity, which reduces cAMP synthesis and PKA-dependent
signalling (Fig. 2). Indeed, activators of adenylyl cyclase or inhibitors
of PKA have been shown to inhibit or occlude long-term eCB-plasticity at
several synapses throughout the brain (Ahumada et al., 2013; Cheva­
leyre et al., 2007; Haj-Dahmane and Shen, 2010; Mato et al., 2008; Park
et al., 2017). PKA is known to phosphorylate the active zone protein
RIM1α (Rab3-interacting molecule 1α), which is thought to promote its
interaction with other members of the active zone matrix and has been
linked to promoting presynaptic LTP (Lonart et al., 2003) although see
(Kaeser et al., 2008a). RIM1α, together with RIM1β (an isoform encoded
by the same gene; Kaeser et al., 2008b), are part of a diverse family of
multidomain adapter proteins that form a scaffold for various key pre­
synaptic proteins including: 14-3-3, Munc13-1, Munc18-1, synapto­
tagmin and VGCCs, which together dock synaptic vesicles to exocytotic
machinery and prime them for fusion and release (Fig. 2; see also Gar­
cia-Junco-Clemente et al., 2005; Ziv and Garner, 2004 for comprehen­
sive reviews on active zones). Interestingly, eCB-iLTD in the
hippocampus was abolished in RIM1α− /- and RIM1αβ− /- mice, suggest­
ing CB1R-regulation of RIM1α (via inhibition of PKA) might be
responsible for underlying the sustained decrease in probability of pre­
synaptic release (Chevaleyre et al., 2007; Kaeser et al., 2008b). This was
the first direct indication that eCB-plasticity might result from altered
presynaptic release machinery and it is now becoming increasingly clear
that CB1Rs can significantly alter the active zone matrix (Fig. 2; Alonso
et al., 2017; Glebov et al., 2017; Monday et al., 2020; Njoo et al., 2015;
Wang et al., 2018). However, RIM1 does not appear to be a requirement
for all eCB-plasticity, for example at corticostriatal synapses, while
conditional knock-out of RIM1αβ from excitatory neurons impairs gen­
eral synaptic transmission, eCB-LTD remained comparable to controls
(Kupferschmidt et al., 2019). It is therefore likely that the precise mo­
lecular underpinnings of eCB-plasticity may vary between synapses at
different brain regions. Other mechanisms that involve changes to active
zone proteins downstream of CB1R activation and may be implicated in
eCB-plasticity include: ERK-dependent phosphorylation of Munc18-1
(Schmitz et al., 2016; Wang et al., 2018) and reduced cAMP activation
of Epac2 (guanine nucleotide exchange proteins activated by
cAMP)/PLC signalling, which was linked to decreased RIM1α content at
active zones and CB1R-dependent silencing of cerebellar granule cells
(Alonso et al., 2017; Ramirez-Franco et al., 2014).
4.3.1.1. A role for protein synthesis-dependent disassembly of the active
zone matrix in eCB-LTD?. Of particular interest is the finding that long-
term eCB-plasticity is dependent on presynaptic protein synthesis, a
characteristic that is distinct from short-term eCB-plasticity (Adermark
et al., 2009; Monday et al., 2020; Navakkode and Korte, 2014; Yin et al.,
2006; Younts et al., 2016). This has been demonstrated in the hippo­
campus (Monday et al., 2020; Navakkode and Korte, 2014; Younts et al.,
2016) and the striatum (Adermark et al., 2009; Yin et al., 2006),
although see (Jung et al., 2012) who find eCB-LTD in the nucleus
accumbens is independent of protein synthesis. In two sequential studies
by the same group, an intricate signalling pathway has recently been
identified downstream of CB1R activation, which links protein synthesis
14
Neuropharmacology 197 (2021) 108736
to decreased actin assembly, resulting in a reduced active zone matrix,
reduction in axon bouton density and eCB-iLTD in the hippocampus
(Fig. 2; Monday et al., 2020; Younts et al., 2016). It was found that
eCB-iLTD requires cap-dependent protein synthesis, which was upre­
gulated by a mechanism involving mTOR (mammalian target of rapa­
mycin) (Younts et al., 2016), likely via CB1R-activation of PI3K/Akt
pathways (Gomez et al., 2011). mTOR is a serine/threonine kinase that
upon activation, nucleates two distinct multiprotein complexes
(mTORC1 and mTORC2), which are involved in numerous cell processes
including cap-dependent protein synthesis and ribosome biogenesis
(Laplante and Sabatini, 2009). Intriguingly, downstream of CB1R-mTOR
activation, the expression level of several proteins was increased, many
of which play key roles in ubiquitin-proteosomal degradation (Monday
et al., 2020). Conversely, expression of proteins associated with the
WAVE1 regulatory complex (a complex of proteins that promotes the
assembly of actin filaments), such as ARPC2 (an essential component of
the Arp2/3 complex required for actin polymerisation and assembly),
were decreased by CB1R activation (Monday et al., 2020). This finding is
particularly intriguing as it suggests eCB-CB1R controls presynaptic
proteostasis, a homeostatic mechanism that balances protein synthesis
and degradation, which is vital for neuronal function and synaptic
plasticity (Hanus and Schuman, 2013). Further, it was found that actin
remodelling via CB1R-inhibition of Rac1, a GTPase that is required to
expose the VCA region of the WAVE1 complex to promote Arp2/3 as­
sembly and actin polymerisation, is a requirement for iLTD expression
(Monday et al., 2020). Of particular note, whilst CB1R activation
induced a reduction in synaptic bouton size, this was not a requirement
of eCB-iLTD. Instead, inhibitors of ubiquitination completely prevented
iLTD expression. It was suggested that ubiquitination may prevent
Arp2/3 and other integral presynaptic proteins from interacting with
their binding partners, which leads to actin depolymerisation and
eventually a decrease in bouton density (Monday et al., 2020). This
process involves highly intricate signalling pathways that are not fully
defined; however, it demonstrates the potential for eCB-CB1R signalling
to significantly alter both the signalling within presynaptic active zones
as well as presynaptic bouton density (Fig. 2). This would be expected to
markedly downregulate presynaptic function and could play a role in
retraction of synaptic inputs. It remains to be seen whether this process
is specific to inhibitory hippocampal synapses or whether it is common
to brain wide eCB-plasticity.
4.3.1.2. Can CB1Rs bidirectionally alter the active zone matrix to promote
eCB-LTP?. Intriguingly, and in contrast to the findings detailed above,
recent evidence suggests downstream CB1R signalling may produce
bidirectional effects on the active zone matrix. Indeed, eCB-facilitation
of LTP at lateral perforant path inputs to dentate gyrus neurons of the
hippocampus was shown to be dependent on a novel signalling pathway
that involves CB1R activation of the integrin-associated tyrosine kinase
FAK (focal adhesion kinase) and subsequent activation of Rho/ROCK
(RhoA associated coiled coil containing kinase 2) signalling to promote
presynaptic actin remodelling and presumably enhance neurotrans­
mitter release (Wang et al., 2016, 2018; see Hanna and El-Sibai, 2013;
Schmandke et al., 2007 for comprehensive reviews on Rho/ROCK sig­
nalling pathways and the control of actin dynamics). Remarkably,
facilitated LTP was independent of GABAergic activity and thus could
not be explained by a disinhibition mechanism (Wang et al., 2016).
Rather, these findings indicate a novel mechanism in which CB1R ac­
tivity may directly enhance the probability of presynaptic neurotrans­
mitter release. These findings are surprising given the wealth of
evidence indicating CB1R activation reduces presynaptic strength (see
discussion above). Whether this is a brain-wide mechanism or restricted
to this particular synapse, remains to be seen. It is also not clear whether
this is mediated by Gαi/o-signalling or whether it results from an alter­
native G-protein coupling to CB1Rs. In this regard, CB1R-dependent LTP
at corticostriatal synapses was found to be dependent on presynaptic
B.L. Winters and C.W. Vaughan
activation of PKA, suggesting CB1Rs may couple to Gαs in this instance
(Cui et al., 2016). Alternatively, CB1Rs expressed in astrocytes are
coupled to Gαq/11 and induce LTP of neighbouring hippocampal CA1
neurons via a mechanism that involves Ca2+-dependent glutamate
release from astrocytes, which acts at presynaptically expressed
NMDARs or group I mGluRs to increase the probability of neurotrans­
mitter release (Gomez-Gonzalo et al., 2015; Navarrete and Araque,
2008, 2010). Indeed, substantial evidence supports the idea that CB1Rs
are promiscuous with their G-protein coupling, with evidence support­
ing coupling to Gαq/11, Gαs, Gαz and Gα12/13 throughout various brain
regions (Caballero-Floran et al., 2016; Diez-Alarcia et al., 2016; Glass
and Felder, 1997; Navarrete and Araque, 2008; Prather et al., 2000).
Despite this, the functional relevance of this heterogeneity in G-protein
coupling is not well defined and is likely cell-type specific (discussed in
Busquets-Garcia et al., 2018; Busquets-Garcia et al., 2015). Adding
further complexity to the downstream signalling of CB1Rs is the possi­
bility of heterodimerisation with other GPCRs. In this regard, the func­
tional interplay between dopamine D2R determines whether CB1Rs
signal via Gαi/o or Gαs (Glass and Felder, 1997). Therefore, while most of
the evidence supports canonical CB1R Gαi/o-signalling as the main
mechanism underlying eCB-plasticity, there is considerable propensity
for atypical CB1R signalling to distinctly alter synaptic efficacy. Future
studies that address the nuances of CB1R coupling under different
physiological and pathological conditions would considerably increase
our understanding of the eCB system function and could uncover pos­
sibilities for specific pharmacological interventions against neurological
disorders.
4.3.1.3. Towards a better understanding of presynaptically expressed eCB-
plasticity. To date, studying mechanisms that underlie changes in pre­
synaptic function has been inherently difficult. This is due to the paucity
of techniques that are able to resolve presynaptic nanoarchitecture and
signalling dynamics in real time. Traditional techniques such as electron
microscopy provide ultrastructural resolution of machinery contained
within pre- and postsynaptic compartments but are limited in their
ability to give functional context. Conversely, paired electrophysiolog­
ical recordings of synaptically connected neurons allows selective
(usually pharmacological) manipulations to the pre- and post-synapse
and provides functional context. However, this technique is extremely
challenging, particularly in brain slices which – outside of in vivo re­
cordings – offers the closest to physiologically relevant conditions to
study synaptic plasticity. Indeed, the synapse of interest is limited to
between two neurons that are contained within the sliced tissue and
manipulations are limited by the selectivity and availability of phar­
macological (or other) reagents. Following the advent of super-
resolution fluorescent imaging techniques such as STORM (stochastic
optical reconstruction microscopy), PALM (photoactivatable local­
isation microscopy), STED (stimulated emission depletion microscopy)
and SIM (structured illumination microscopy), live cell imaging of pre­
synaptic machinery is now possible (see Nosov et al., 2020; Tonnesen
and Nagerl, 2013 for reviews). Although these technologies are >10–15
years old (Tonnesen and Nagerl, 2013), their use in studying presynaptic
dynamics during eCB-plasticity is still in its infancy. Combining these
techniques with sophisticated genetic manipulations, will offer
extremely powerful methods to fully interrogate the presynaptic
mechanisms underlying eCB-plasticity. Therefore, while our current
understanding is relatively limited, future studies in this regard are
eagerly anticipated to resolve the many unanswered questions regarding
the intricate presynaptic signalling mechanisms governing
eCB-plasticity.
4.3.2. Integration with other presynaptic signalling mechanisms
Whilst it is important to fully characterise downstream signalling of
CB1Rs, as we previously stated, in many cases, activation of CB1Rs alone
is not sufficient to induce eCB-plasticity (see section 4.2.1). Therefore,
15
Neuropharmacology 197 (2021) 108736
some other presynaptic mechanism that acts synergistically with CB1R
signalling is likely required. However, this ‘additional’ presynaptic
signal is poorly defined. Firstly, it is not clear whether this signal is
homosynaptic (i.e. contained within the synapse that is undergoing eCB-
plasticity) or whether other neuromodulator signalling from hetero­
synaptic inputs might play a role. Secondly, it is not clear whether the
signal is required to work in concert with CB1R signalling to facilitate the
induction of eCB-plasticity (e.g. by synergistically feeding into Gαi/o-
pathways) or whether it indirectly alters mechanisms that facilitate the
expression of eCB-plasticity (e.g. by altering or priming the active zone/
release machinery). It is likely a combination of all possible factors plays
a role, and this varies depending on both overall network activity and
the neuronal activity profile within a particular microcircuit. Thus,
identifying the exact presynaptic conditions that favour eCB-plasticity
has been particularly challenging, which likely reflects the subtle role
eCBs play in regulating a dynamic network.
Despite these challenges, a prominent candidate for this additional
presynaptic signal is the influx of presynaptic calcium either via pre­
synaptically expressed NMDARs (Andrade-Talavera et al., 2016; Bender
et al., 2006; Heifets et al., 2008; Singla et al., 2007; Sjostrom et al.,
2003), or perhaps through patterns of action-potential driven activation
of presynaptic VGCCs (see in Adermark et al., 2009). Although the
precise function of this calcium signal is not well defined, it likely in­
volves calcium sensors such as the calcium/calmodulin-dependent
phosphatase calcineurin (also known as PP2B), the activity of which
was required for eCB-LTD at both hippocampal and corticostriatal syn­
apses (Andrade-Talavera et al., 2016; Cui et al., 2016; Heifets et al.,
2008). Calcineurin is a serine/threonine phosphatase that is often
associated with postsynaptic signalling and is involved in multiple
pathways implicated in synaptic plasticity, one of which is the regula­
tion of postsynaptically expressed VGCCs (L-type, CaV1.2/1.3) (Peterson
et al., 1999; Yakel, 1997; Zuhlke et al., 1999). Both calcineurin and
CaV1.2 exist in a molecular complex mediated by the scaffolding protein
AKAP79/150 (A-Kinase anchoring proteins), which together with PKA
and calmodulin bidirectionally regulate the activity of CaV1.2 (Dittmer
et al., 2014; Oliveria et al., 2012). However, at presynaptic sites, the role
of calcineurin is less clear. Calcineurin, RIM1 and other components of
the active zone matrix are known to form part of a macromolecular
complex that constitutes so called the ‘VGCC nanodomain’, suggesting
they may act to regulate VGCC activity as well as synaptic vesicle
exo/endocytosis (Muller et al., 2010; see also in Nanou and Catterall,
2018 & Gandini and Zamponi, 2021). Indeed, calcineurin – together
with cyclin-dependent kinase 5 (cdk5), are known to play a role in
governing synaptic vesicle cycling, which may involve changing the
interaction between P/Q- (CaV2.1) or N-type (CaV2.2) VGCCs with RIM1
or other release machinery (Kim and Ryan, 2013; Su et al., 2012;
Tomizawa et al., 2002; also reviewed in Dolphin and Lee, 2020; Fassio
et al., 2016). Yet these reports disagree on whether calcineurin/cdk5
facilitate or impair VGCC activity (Kim and Ryan, 2013; Su et al., 2012).
In fact, inhibition of calcineurin was shown to dramatically reduce
action-potential induced calcium influx and exocytosis in cultured hip­
pocampal neurons (Kim and Ryan, 2013), whilst in dorsal root ganglion
neurons, calcineurin acted to downregulate P/Q- and N-type currents
following TRPV1 activation (Wu et al., 2005). The reason for this
discrepancy is unclear and might reflect the different routes of calcium
entry (voltage-gated vs ligand-gated ion-channels). Nevertheless, it
demonstrates the complex relationship between the regulatory mecha­
nisms that govern both VGCC activity and the active zone matrix at
presynaptic sites. Thus, relating this back to the context of eCB-plasticity
is difficult to reconcile and requires further work to fully elucidate the
function of pre-synaptic calcium outside its role in stimulating neuro­
transmitter release and the role calcium-dependent proteins, such as
calcineurin, may play in this.
B.L. Winters and C.W. Vaughan
5. Summary & conclusions
Research into the endogenous cannabinoid system has revealed that
it is a near ubiquitous regulator of neuronal communication throughout
the brain. This regulation is observed as the retrograde control of syn­
aptic transmission over short-time scales, and by more complex mech­
anisms over longer-time scales. Despite the widespread nature of eCB
retrograde control, there are substantial regional and synapse-specific
differences. The forms of eCB short- and long-term plasticity differ
across synapses and brain regions. Furthermore, eCB short- and long-
term plasticity are not always readily expressed at the same synapse.
Nonetheless, the key difference between short- and long-term eCB-
plasticity appears to reside with the duration of CB1R activation and
other yet to be defined presynaptic signalling cascades.
We are only beginning to fully understand the processes involved in
promoting long-term changes in synaptic efficacy that are dependent on
eCB-signalling. While the mechanisms of eCB synthesis are relatively
well defined, beyond the synergistic interaction of these mechanisms, it
is not clear what else across the pre-/post-synaptic domains may pro­
mote sufficient eCB synthesis or sustained CB1R activity necessary for
induction of eCB-plasticity. Similarly, the mechanisms downstream of
CB1R activation that result in persistent reduction in neurotransmitter
release remain poorly understood. Further research is needed to fully
understand the integration of CB1R signalling with other presynaptic
activity which might alter assembly of the active zone matrix. Here we
have detailed several key avenues for further research that have sig­
nificant potential in governing eCB-plasticity. Those that concern
‘atypical’ CB1R signalling, such as from intracellular compartments, or
via mechanisms that are outside of Gαi/o-dependent pathways are
particularly intriguing and attest to the intricacy of the eCB system.
Acknowledgements
This study was supported by the Ernest Heine Family Foundation and
Pain Foundation.
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