title: Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling.
abstract: Mutations in several postsynaptic proteins have recently been implicated in the molecular pathogenesis of autism and autism spectrum disorders (ASDs), including Neuroligins, Neurexins, and members of the ProSAP/Shank family, thereby suggesting that these genetic forms of autism may share common synaptic mechanisms. Initial studies of ASD-associated mutations in ProSAP2/Shank3 support a role for this protein in glutamate receptor function and spine morphology, but these synaptic phenotypes are not universally penetrant, indicating that other core facets of ProSAP2/Shank3 function must underlie synaptic deficits in patients with ASDs. In the present study, we have examined whether the ability of ProSAP2/Shank3 to interact with the cytoplasmic tail of Neuroligins functions to coordinate pre/postsynaptic signaling through the Neurexin-Neuroligin signaling complex in hippocampal neurons of Rattus norvegicus. Indeed, we find that synaptic levels of ProSAP2/Shank3 regulate AMPA and NMDA receptor-mediated synaptic transmission and induce widespread changes in the levels of presynaptic and postsynaptic proteins via Neurexin-Neuroligin transsynaptic signaling. ASD-associated mutations in ProSAP2/Shank3 disrupt not only postsynaptic AMPA and NMDA receptor signaling but also interfere with the ability of ProSAP2/Shank3 to signal across the synapse to alter presynaptic structure and function. These data indicate that ASD-associated mutations in a subset of synaptic proteins may target core cellular pathways that coordinate the functional matching and maturation of excitatory synapses in the CNS.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94304, USA.
authors.forename: Magali H
authors.initials: MH
authors.lastname: Arons
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Thynne
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Grabrucker
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Schoen
authors.forename: Juliette E
authors.initials: JE
authors.lastname: Cheyne
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Boeckers
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Montgomery
authors.forename: Craig C
authors.initials: CC
authors.lastname: Garner
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D057907:Post-Synaptic Density / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D009435:Synaptic Transmission / Q000235:genetics*; D014162:Transfection; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D015820:Cadherins; D002352:Carrier Proteins; D015816:Cell Adhesion Molecules, Neuronal; D018691:Excitatory Amino Acid Antagonists; C092350:FM 4-64; D009419:Nerve Tissue Proteins; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; C492357:SHANK3 protein, human; D050598:Vesicular Glutamate Transport Protein 1; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione