Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan–McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice. Genomic studies have identified numerous candidate genes for autism spectrum disorders, many of which encode synaptic proteins. One of the most promising is Shank3, which codes for a key post-synaptic density protein at glutamatergic synapses. Peça et al. show that mice with Shank3 deletions display several features of autism, including social deficits, as well as abnormal striatal synapses and cortico-striatal circuitry. The findings demonstrate a crucial role for Shank3 in neuronal connectivity and provide a mechanism for its possible function in autistic-like behaviours.