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Cell Rep. 2015 Jun 9;11(9):1400-1413. doi: 10.1016/j.celrep.2015.04.064. Epub 2015 May 28.

Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators.

Author information

1
Department of Physiology & Biophysics, State University of New York at Buffalo, Buffalo, NY, 14214.
2
Department of Pharmacology & Toxicology, State University of New York at Buffalo, Buffalo, NY, 14214.
3
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.
#
Contributed equally

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.

PMID:
26027926
PMCID:
PMC4464902
DOI:
10.1016/j.celrep.2015.04.064
[Indexed for MEDLINE]
Free PMC Article

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