title: Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators.
abstract: Haploinsufficiency of the Shank3 gene, which encodes a scaffolding protein at glutamatergic synapses, is a highly prevalent and penetrant risk factor for autism. Using combined behavioral, electrophysiological, biochemical, imaging, and molecular approaches, we find that Shank3-deficient mice exhibit autism-like social deficits and repetitive behaviors, as well as the significantly diminished NMDA receptor (NMDAR) synaptic function and synaptic distribution in prefrontal cortex. Concomitantly, Shank3-deficient mice have a marked loss of cortical actin filaments, which is associated with the reduced Rac1/PAK activity and increased activity of cofilin, the major actin depolymerizing factor. The social deficits and NMDAR hypofunction are rescued by inhibiting cofilin or activating Rac1 in Shank3-deficient mice and are induced by inhibiting PAK or Rac1 in wild-type mice. These results indicate that the aberrant regulation of synaptic actin filaments and loss of synaptic NMDARs contribute to the manifestation of autism-like phenotypes. Thus, targeting actin regulators provides a strategy for autism treatment.
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Buffalo, Buffalo, NY, 14214.
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Duffney
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Buffalo, Buffalo, NY, 14214.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhong
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Buffalo, Buffalo, NY, 14214.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Buffalo, Buffalo, NY, 14214.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Matas
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Buffalo, Buffalo, NY, 14214.
authors.forename: Jia
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Buffalo, Buffalo, NY, 14214.
authors.forename: Luye
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Buffalo, Buffalo, NY, 14214.
authors.forename: Kaijie
authors.initials: K
authors.lastname: Ma
authors.affiliation: Department of Pharmacology & Toxicology, State University of New York at Buffalo, Buffalo, NY, 14214.
authors.forename: David M
authors.initials: DM
authors.lastname: Dietz
authors.affiliation: Seaver Autism Center for Research and Treatment, Department of Psychiatry, Friedman Institute and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kajiwara
authors.affiliation: Seaver Autism Center for Research and Treatment, Department of Psychiatry, Friedman Institute and Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.affiliation: Department of Physiology & Biophysics, State University of New York at Buffalo, Buffalo, NY, 14214.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000503:physiopathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D051339:Actin Depolymerizing Factors; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; C492356:Shank3 protein, mouse; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein