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Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling.
J Neurosci. 2012 Oct 24; 32(43):14966-78.JN

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+Show Affiliations

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94304, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

23100419

Citation

Arons, Magali H., et al. "Autism-associated Mutations in ProSAP2/Shank3 Impair Synaptic Transmission and Neurexin-neuroligin-mediated Transsynaptic Signaling." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 32, no. 43, 2012, pp. 14966-78.
Arons MH, Thynne CJ, Grabrucker AM, et al. Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. J Neurosci. 2012;32(43):14966-78.
Arons, M. H., Thynne, C. J., Grabrucker, A. M., Li, D., Schoen, M., Cheyne, J. E., Boeckers, T. M., Montgomery, J. M., & Garner, C. C. (2012). Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 32(43), 14966-78. https://doi.org/10.1523/JNEUROSCI.2215-12.2012
Arons MH, et al. Autism-associated Mutations in ProSAP2/Shank3 Impair Synaptic Transmission and Neurexin-neuroligin-mediated Transsynaptic Signaling. J Neurosci. 2012 Oct 24;32(43):14966-78. PubMed PMID: 23100419.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. AU - Arons,Magali H, AU - Thynne,Charlotte J, AU - Grabrucker,Andreas M, AU - Li,Dong, AU - Schoen,Michael, AU - Cheyne,Juliette E, AU - Boeckers,Tobias M, AU - Montgomery,Johanna M, AU - Garner,Craig C, PY - 2012/10/27/entrez PY - 2012/10/27/pubmed PY - 2013/1/8/medline SP - 14966 EP - 78 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 32 IS - 43 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/23100419/Autism_associated_mutations_in_ProSAP2/Shank3_impair_synaptic_transmission_and_neurexin_neuroligin_mediated_transsynaptic_signaling_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=23100419 DB - PRIME DP - Unbound Medicine ER -