You are here

J Neurosci DOI:10.1523/JNEUROSCI.2533-11.2011

Sapap3 deletion causes mGluR5-dependent silencing of AMPAR synapses.

Publication TypeJournal Article
Year of Publication2011
AuthorsWan, Y, Feng, G, Calakos, N
JournalJ Neurosci
Date Published2011 Nov 16
KeywordsAnimals, Animals, Newborn, Biophysics, Electric Stimulation, Endocytosis, Excitatory Amino Acid Agents, Excitatory Postsynaptic Potentials, Green Fluorescent Proteins, In Vitro Techniques, Mice, Mice, Transgenic, Nerve Tissue Proteins, Patch-Clamp Techniques, Piperidines, Pyrazoles, Receptor, Metabotropic Glutamate 5, Receptors, AMPA, Receptors, Dopamine D1, Receptors, Dopamine D2, Receptors, Metabotropic Glutamate, Statistics, Nonparametric, Synapses, Synaptic Transmission

Synaptic transmission mediated by AMPA-type glutamate receptors (AMPARs) is regulated by scaffold proteins in the postsynaptic density. SAP90/PSD-95-associated protein 3 (SAPAP3) is a scaffold protein that is highly expressed in striatal excitatory synapses. While loss of SAPAP3 is known to cause obsessive-compulsive disorder-like behaviors in mice and reduce extracellular field potentials in the striatum, the mechanism by which SAPAP3 regulates excitatory neurotransmission is largely unknown. This study demonstrates that Sapap3 deletion reduces AMPAR-mediated synaptic transmission in striatal medium spiny neurons (MSNs) through postsynaptic endocytosis of AMPARs. Striatal MSNs in Sapap3 KO mice have fewer synapses with AMPAR activity and a higher proportion of silent synapses. We further find that increased metabotropic glutamate receptor 5 (mGluR5) activity in Sapap3 KO mice underlies the decrease in AMPAR synaptic transmission and excessive synapse silencing. These findings suggest a model whereby the normal role of SAPAP3 is to inhibit mGluR5-driven endocytosis of AMPARs. The results of this study provide the first evidence for the mechanism by which the SAPAP family of scaffold proteins regulates AMPAR synaptic activity.


Alternate JournalJ. Neurosci.
PubMed ID22090495
PubMed Central IDPMC3475185
Grant ListK02 NS054840 / NS / NINDS NIH HHS / United States
NS064577 / NS / NINDS NIH HHS / United States
MH081201 / MH / NIMH NIH HHS / United States
NS054840 / NS / NINDS NIH HHS / United States
NS064577-S1 / NS / NINDS NIH HHS / United States
R01 MH081201 / MH / NIMH NIH HHS / United States
R01 NS064577 / NS / NINDS NIH HHS / United States