title: Sapap3 deletion causes mGluR5-dependent silencing of AMPAR synapses.
abstract: 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.
authors.affiliation: Center for Translational Neuroscience, Division of Neurology, Duke University, Durham, North Carolina 27710, USA.
authors.forename: Yehong
authors.initials: Y
authors.lastname: Wan
authors.forename: Guoping
authors.initials: G
authors.lastname: Feng
authors.forename: Nicole
authors.initials: N
authors.lastname: Calakos
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D004558:Electric Stimulation; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013569:Synapses / Q000187:drug effects / Q000235:genetics*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*
chemical_list: D018683:Excitatory Amino Acid Agents; C578936:Grm5 protein, mouse; D009419:Nerve Tissue Proteins; D010880:Piperidines; D011720:Pyrazoles; D064529:Receptor, Metabotropic Glutamate 5; D018091:Receptors, AMPA; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018094:Receptors, Metabotropic Glutamate; C523020:Sapap3 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C103505:AM 251
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