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

• Shank3 deficiency induces ASD-like behavioral deficits and NMDAR hypofunction in PFC
• Shank3 deficiency leads to reduced synaptic F-actin and altered actin regulators in PFC
• Inhibiting cofilin rescues behavioral and synaptic deficits in Shank3-deficient mice
• Manipulating cortical Rac1 or PAK controls the manifestation of ASD-like phenotypes

SummaryHaploinsufficiency 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.

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