Sapap3 deletion anomalously activates short-term endocannabinoid-mediated synaptic plasticity.

J Neurosci
Authors
Keywords
Abstract

Retrograde synaptic signaling by endocannabinoids (eCBs) is a widespread mechanism for activity-dependent inhibition of synaptic strength in the brain. Although prevalent, the conditions for eliciting eCB-mediated synaptic depression vary among brain circuits. As yet, relatively little is known about the molecular mechanisms underlying this variation, although the initial signaling events are likely dictated by postsynaptic proteins. SAP90/PSD-95-associated proteins (SAPAPs) are a family of postsynaptic proteins unique to excitatory synapses. Using Sapap3 knock-out (KO) mice, we find that, in the absence of SAPAP3, striatal medium spiny neuron (MSN) excitatory synapses exhibit eCB-mediated synaptic depression under conditions that do not normally activate this process. The anomalous synaptic plasticity requires type 5 metabotropic glutamate receptors (mGluR5s), which we find are dysregulated in Sapap3 KO MSNs. Both surface expression and activity of mGluR5s are increased in Sapap3 KO MSNs, suggesting that enhanced mGluR5 activity may drive the anomalous synaptic plasticity. In direct support of this possibility, we find that, in wild-type (WT) MSNs, pharmacological enhancement of mGluR5 by a positive allosteric modulator is sufficient to reproduce the increased synaptic depression seen in Sapap3 KO MSNs. The same pharmacologic treatment, however, fails to elicit further depression in KO MSNs. Under conditions that are sufficient to engage eCB-mediated synaptic depression in WT MSNs, Sapap3 deletion does not alter the magnitude of the response. These results identify a role for SAPAP3 in the regulation of postsynaptic mGluRs and eCB-mediated synaptic plasticity. SAPAPs, through their effect on mGluR activity, may serve as regulatory molecules gating the threshold for inducing eCB-mediated synaptic plasticity.

Year of Publication
2011
Journal
J Neurosci
Volume
31
Issue
26
Pages
9563-73
Date Published
2011 Jun 29
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.1701-11.2011
PubMed ID
21715621
PubMed Central ID
PMC3367431
Links
Grant list
T32NS051156 / NS / NINDS NIH HHS / United States
K02 NS054840 / NS / NINDS NIH HHS / United States
NS064577 / NS / NINDS NIH HHS / United States
K02 NS054840-05 / NS / NINDS NIH HHS / United States
F32 MH084460-01 / MH / NIMH NIH HHS / United States
R01 NS064577-02S1 / NS / NINDS NIH HHS / United States
R01 NS064577-01 / NS / NINDS NIH HHS / United States
T32 NS051156-06 / NS / NINDS NIH HHS / United States
R01 MH081201-01 / MH / NIMH NIH HHS / United States
MH081201 / MH / NIMH NIH HHS / United States
NS054840 / NS / NINDS NIH HHS / United States
T32 NS051156 / NS / NINDS NIH HHS / United States
F32MH084460 / MH / NIMH NIH HHS / United States
R01 MH081201 / MH / NIMH NIH HHS / United States
R01 NS064577 / NS / NINDS NIH HHS / United States
F32 MH084460 / MH / NIMH NIH HHS / United States