Send to

Choose Destination
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

Department of Physiology & Biophysics, State University of New York at Buffalo, Buffalo, NY, 14214.
Department of Pharmacology & Toxicology, State University of New York at Buffalo, Buffalo, NY, 14214.
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


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center