Bertran-Gonzalez, Jesus

Napier, Ian A

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Toward a Model of Retrograde Regulation of Striatal
Synaptic Depression
Jesus Bertran-Gonzalez and Ian A. Napier
Brain and Mind Research Institute, The University of Sydney, New South Wales 2050, Australia
Review of Tozzi et al.
As the primary input nucleus of the basal
ganglia, the striatum receives considerable
glutamatergic information from cortical
and thalamic neurons. Most striatal neu-
rons (95%) are GABAergic medium-
sized spiny neurons (MSNs),which can be
subdivided into two populations accord-
ing to their projection targets and their
selective expression of dopamine receptor
types. StriatonigralMSNs express D1-type
receptors (D1Rs) and constitute the direct
pathway of the basal ganglia, whereas stri-
atopallidal MSNs express D2-type recep-
tors (D2Rs) and constitute the indirect
pathway.
An important form of plasticity com-
monly observed in striatalMSNs, regardless
of their projection targets and dopamine
receptor types expressed, is a long-lasting
reduction of synaptic strength in their ex-
citatory glutamatergic inputs [i.e., long-
term depression (LTD)] (Calabresi et al.,
1992). LTD in MSNs appears to be initi-
ated by postsynaptic endocannabinoid
(eCB) synthesis, which acts as a retrograde
signal to reduce glutamate release by acti-
vating presynaptic CB1 receptors (CB1Rs).
eCB-mediated striatal LTD is strongly de-
pendent upon D2R stimulation, as well as
group Imetabotropic glutamate receptors
(mGluR1/5) and L-type Ca
2 channels
(for review, see Di Filippo et al., 2009).
This leaves an important question unan-
swered: how does a postsynaptically initiated,
D2R-dependent phenomenon induceLTD in
allMSNsifD2Rsareexpressed inonlyasubset
of these neurons? Recent studies have at-
tempted to address this question (Wang et al.,
2006;Kreitzer andMalenka, 2007;Tozzi et al.,
2011).
Wang et al. (2006) suggested that the rel-
evant D2Rs mediating striatal LTD were
those expressed in cholinergic interneurons
that, despite their low abundance (5%),
project to virtually all MSNs. In their pro-
posed model, stimulation of D2Rs in these
neurons decreases their firing rate, reducing
both acetylcholine (Ach) release and M1-
typemuscarinicAch receptor (M1R) stimu-
lation. Postsynaptic M1Rs are located near
glutamatergic synapses in both direct and
indirect pathway MSNs and they inhibit
L-type Ca2 channels (Olson et al., 2005).
Therefore, transient interruption of the
tonic Ach-mediated M1R stimulation
would be expected to lead to increased in-
tracellular Ca2 concentration and local
eCB release inMSNs, which in turnwould
stimulate presynaptic CB1Rs reducing
glutamatergic drive in synapses onto both
striatonigral and striatopallidal MSN
populations.
Contrary to this view, Kreitzer and
Malenka (2007) reported that glutamatergic
synapses onto D2R-expressing MSNs were
more excitable than those formed onto
D1R-expressing MSNs, and that D2R
stimulation led to eCB-mediated LTD ex-
clusively in striatopallidal neurons, high-
lighting the role of postsynaptic D2Rs in
striatal LTD. Selective striatopallidal eCB-
LTD was also found after mGluR1/5 stimu-
lation, which led Kreitzer and Malenka
(2007) to conclude that eCB-mediated LTD
wasmore likely tooccur in indirect pathway
neurons.
In a recent paper published in The
Journal of Neuroscience, Tozzi et al. (2011)
provide a model of D2R-dependent eCB-
mediated LTD that could potentially rec-
oncile the aforementioned studies. The
main feature of the Tozzi et al. (2011)
model is the involvement of the adenosine
A2A receptors (A2ARs), which are highly
enriched in the striatum and tightly coun-
teract D2Rs at multiple levels (Schiffmann
et al., 2007). Importantly, A2ARs are not
only selectively expressed in D2R-expre-
ssing striatopallidalMSNs, but are also ex-
pressed presynaptically on corticostriatal
and thalamostriatal terminals, where they
are thought tomodulate glutamate release
(Schiffmann et al., 2007; Ferre´ et al.,
2010). Although Tozzi et al. (2011) also
examined responses in dopamine-deple-
ted striatal slices (a model of Parkinson’s
disease), here we will focus on their find-
ings in physiological conditions.
In the first set of experiments, Tozzi et al.
(2011) studied the involvementofD2Rs and
A2ARs ineCB-mediated synapticdepression
in ex vivo striatal rat slices (Tozzi et al., 2011,
their Fig. 1). They performed both intracel-
lular and whole-cell patch-clamp record-
ings from MSNs of the dorsal striatum.
ReceivedMarch 4, 2011; revisedMarch 29, 2011; acceptedMarch 31, 2011.
We thank Prof. M. J. Christie, Prof. B.W. Balleine, and Dr.M.Matamales
for their valuable comments on the text.
Correspondence should be addressed to Jesus Bertran-Gonzalez, Be-
havioural Neuroscience Laboratory, Brain andMind Research Institute, The
University of Sydney, NSW, 2050, Australia. E-mail: j.bertran-gonzalez@
sydney.edu.au.
DOI:10.1523/JNEUROSCI.1133-11.2011
Copyright © 2011 the authors 0270-6474/11/316944-03$15.00/0
6944 • The Journal of Neuroscience, May 11, 2011 • 31(19):6944–6946
Single 0.1 Hz stimulations of corticostria-
tal fibers (in the presence of GABAA re-
ceptor antagonist bicuculline) were used
to induce EPSPs and EPSCs. Once stable
recordings were established, the D2R ago-
nist quinpirole was applied either alone or
in combination with two different A2AR
antagonists [ZM24138 (ZM) or ST1535
(ST)]. Long-lasting depression of EPSP
and EPSC amplitudes, reflecting a decrease
in striatal glutamatergic transmission, was
produced only when D2R agonist and an
A2AR antagonist were coapplied. Impor-
tantly, LTD responses were largely pre-
vented by the CB1R antagonist AM251,
pointing to eCB involvement in this process
(Fig. 1).
In view of the controversy reviewed
above, the authors sought to determine
whether D2R/A2AR modulation differen-
tially affected synaptic activity in terminals
synapsing onto either D2-striatopallidal or
D1-striatonigral neurons (Tozzi et al., 2011,
their Fig. 2). As with the aforementioned
studies, Tozzi et al. (2011) took advan-
tage of bacterial artificial chromosome
(BAC) transgenicmice, a tool that allowsan
accurate identification of neuronal popula-
tions in situ (Gong et al., 2003). These mice
hold a BAC transgene in which EGFP ex-
pression is regulated by D1 receptor (D1-
EGFP line) orD2R (D2-EGFP line)promoter
sequences, offering a clear visualization of
D1-striatonigral and D2-striatopallidal
MSNs, respectively. In these mice, equiv-
alent reductions of EPSC amplitude were
observed in D1-EGFP and D2-EGFP MSNs
when quinpirole and ZM were coapplied.
Furthermore, the sameproportion (70%)
of D1- and D2-EGFP neurons showed de-
pressed glutamatergic transmission. These
results indicate that concomitant mod-
ulation of D2 and A2A receptors influ-
ences plasticity to the same extent in
bothMSN populations (Fig. 1), in direct
contrast to the observations of Kreitzer
and Malenka (2007).
To further elucidate the involvement of
the eCB system and to confirm a change in
presynaptic release, the authors next per-
formed a series of paired-pulse electrophys-
iology experiments in ex vivo striatal rat
slices (Tozzi et al., 2011, their Fig. 3). When
quinpirole and ZM or ST were coapplied,
the EPSC paired-pulse ratio increased,
suggesting a decrease of glutamate release
probability. Importantly, CB1R antago-
nist AM251 blocked this effect, pointing
to a direct eCB/CB1R involvement in this
process. The role of presynaptic CB1R was
further confirmed through occlusion ex-
periments, in which the CB1R agonist
WIN reduced EPSC amplitude by itself,
an effect that was not strengthened by co-
application of quinpirole and ZM.
Finally, Tozzi et al. (2011) performed
Ca2 buffering studies to explore a possible
link between the pharmacological effects of
D2R/A2AR and eCB retrograde diffusion.
Interestingly, inclusion of BAPTA (a Ca2
chelating agent) in the patch pipette com-
pletely prevented the synaptic depression
induced by quinpirole plus ZM. Indeed, al-
though not discussed by the authors, quin-
pirole plus ZM application appeared to
initially enhance EPSC amplitude (Tozzi et
al., their Fig. 3C). Importantly, intracellular
BAPTA did not prevent the intrinsic effects
of the CB1R and GABABR agonists WIN
and baclofen on EPSC amplitude. Alto-
gether, these results point to the eCB system
as the keymediator of the reduction of syn-
aptic glutamate transmission on presynap-
tic terminals. As illustrated in Figure 1, this
process requires a postsynaptic increase of
intracellular Ca2 in MSNs promoted by
D2R and A2AR modulation (Fig. 1, white
numbered pathway).
As mentioned above, previous studies
have described an involvement of cholin-
ergic interneurons in D2-dependent and
Figure 1. Model of striatal plasticity induced in glutamatergic synapses onto both striatonigral and striatopallidal MSN pop-
ulations in response to concomitant D2 and A2A receptormodulation. Coadministration of D2 receptor agonist [quinpirole (Quin)]
and A2A receptor antagonist (ZM or ST) can induce sustained reduction of glutamate release in striatonigral and striatopallidal
MSNs through at least three different sequences of events (white, blue, and gray numbered pathways). Postsynapticmodulation
of D2/A2A receptors in striatopallidal neuronsmay reduce glutamate release (2Glut) through local retrograde endocannabinoid
signal (white pathway, 1–3). In parallel, blockade of presynaptic A2A receptors located in glutamatergic terminals onto cholinergic
interneurons, plus stimulation of D2 receptors expressed in these neurons, may interrupt their firing, ultimately leading to decreased
acetylcholine release (2Ach,bluepathway,1–3). The reducedstimulationofM1 receptorsmayremovethe inhibitionexertedonL-type
Ca2 channels, promoting calcium influx, endocannabinoid production, and reducedglutamate release onto bothpopulations ofMSNs
(blue pathways 4–6). Finally, blocking presynaptic A2A receptors located in glutamatergic terminals onto striatonigralMSNsmay addi-
tionally reducetheprobabilityof releaseat thesesynapses (graypathway,1and2).Notethat,under this scheme,glutamatergic synapses
onto both striatonigral and striatopallidal neurons receive at least two different signals that reduce release, in agreement with the
equivalent decrease of glutamatergic transmission foundby Tozzi et al. (2011) in bothMSNpopulations.
Bertran-Gonzalez and Napier • Retrograde Regulation of Striatal Synaptic Depression J. Neurosci., May 11, 2011 • 31(19):6944–6946 • 6945
eCB-mediated LTD in both striatonigral
and striatopallidal MSNs (Wang et al.,
2006). To explore whether their observed
effect was related to acetylcholinergic
neurotransmission, Tozzi et al. (2011)
performed whole-cell recordings on cho-
linergic interneurons and showed that the
combination of low-dose quinpirole and
ZM reduced the interneurons’ tonic firing
rate (Tozzi et al., 2011, their Fig. 7). Fur-
ther, the authors demonstrated that inhi-
bition of M1Rs by pirenzepine prevented
EPSC amplitude reduction in MSNs by
quinpirole and ZM, an effect that was
again rescued by WIN (Tozzi et al., 2011,
Fig. 8). In agreement with previous re-
ports (Wang et al., 2006), these findings
implicate cholinergic interneurons in the
propagation of D2R-dependent synaptic
plasticity to all MSN populations and
highlight the role of A2AR in this process.
This mechanism involves postsynaptic
M1Rs, which, through L-type Ca
2 chan-
nels, may ultimately lead to eCB forma-
tion and retrograde signaling (Fig. 1, blue
numbered pathway).
In building a model encompassing their
findings, Tozzi et al., 2011, hypothesized
that D2R and A2AR are coexpressed on stri-
atal cholinergic interneurons, a possibility
that was confirmed by triple immunofluo-
rescence studies, in which D2R and A2AR
were colabeled in combination with a
marker for cholinergic interneurons (Tozzi
et al., 2011, their Fig. 6). However, these re-
sults should be considered carefully, since
D2R and A2AR were detected with primary
antibodies from the same host, a delicate
method that relies on the monovalency of
the Fab fragment to prevent cross-reactivity,
but thatmayproduce interference if not sat-
urated properly (Owen et al., 2010).Despite
D2R expression in striatal cholinergic in-
terneurons being quite clear, A2AR expres-
sion in these neurons is not. In fact, the
restricted expression of A2AR exclusively in
enkephalin-positive striatopallidal MSNs
has been convincingly demonstrated
(Schiffmann et al., 2007; Ferre´ et al., 2010)
and strong evidence against its expression in
cholinergic interneurons has recently been
provided (Durieux et al., 2009). In the latter
work, the authors genetically ablated all
striatal neurons that express the adora2a
(A2AR) gene, clearly showing that only stri-
atopallidal neurons degenerate, whereas all
types of interneurons, including cholinergic
interneurons, remain unaltered (Durieux et
al., 2009, their supplemental Fig. 4).
Nevertheless, it is possible to reconcile
Tozzi et al.’s (2011) results, and probably
those obtained in the previous studies, by
considering the presynaptic distribution of
A2ARs in glutamatergic terminals, in addi-
tion to their postsynaptic expression in D2-
striatopallidal MSNs (Fig. 1, blue and gray
numbered pathways). A2ARs may indeed
follow a defined pattern of presynaptic dis-
tributionand somodulate glutamate release
in direct-pathway corticostriatonigral and
thalamostriatal terminals (Schiffmannet al.,
2007; Ferre´ et al., 2010). In line with this
view, thalamostriatal terminals have re-
cently been shown to regulate cholinergic
interneuron bursting activity in response to
salient stimuli, and this modulates the gat-
ing of corticostriatal activity and the selec-
tive recruitment of D2-striatopallidalMSNs
to drive attentional shift (Ding et al., 2010).
All together, emerging studies are clari-
fying the difficult problem of how a signal
initiated ina subsetof striatalneurons is able
to propagate to all MSNs. As outlined by
Tozzi et al. (2011), this complex regulation
likely involves almost all known neuro-
modulatory systems operating in the stria-
tum, from the primary dopamine signal to
local eCB-mediated retrograde transmis-
sion, going through more tonically propa-
gating signals such as the adenosinergic and
acetylcholinergic systems.
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6946 • J. Neurosci., May 11, 2011 • 31(19):6944–6946 Bertran-Gonzalez and Napier • Retrograde Regulation of Striatal Synaptic Depression


Toward a model of retrograde regulation of striatal synaptic depression.

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Toward a model of retrograde regulation of striatal synaptic depression.

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