[PDF][PDF] Autism-like deficits in Shank3-deficient mice are rescued by targeting actin regulators

LJ Duffney, P Zhong, J Wei, E Matas, J Cheng, L Qin… - Cell reports, 2015 - cell.com
LJ Duffney, P Zhong, J Wei, E Matas, J Cheng, L Qin, K Ma, DM Dietz, Y Kajiwara
Cell reports, 2015cell.com
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 …
Summary
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.
cell.com