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. Autism and autism spectrum disorders (ASDs) are neurodevelopmental disorders diagnosed based on a triad of criteria: deficits in communication, impaired social interaction, and repetitive or restricted interests and behaviours 1 . ASDs are highly heritable disorders with concordance rates as high as 90% for monozygotic twins 2 . Recent genetic and genomic studies have identified a large number of candidate genes for ASDs 3 , many of which encode synaptic proteins 4–6 , indicating synaptic dysfunction may have a critical role in ASDs 7,8 . One of the most promising ASD candidate genes is Shank3, which codes for a key postsynaptic density (PSD) protein at glutamatergic synapses. Disruption of Shank3 is thought to be the cause of core neurodevelopmental and neurobehavioural deficits in the 22q13 deletion syndrome (Phelan–McDermid syndrome), an autism spectrum disorder 9–11 . Furthermore, recent genetic screens have identified several mutations/rare variants of the Shank3 gene in ASD patients outside of diagnosed 22q13 deletion syndrome 12,13 . The Shank family of proteins (SHANK1–3) directly bind SAPAP (also known as DLGAP) to form the PSD-95–SAPAP–SHANK complex 14,15 (PSD-95 is also known as DLG4). This core of proteins is thought to function as a scaffold, orchestrating the assembly of the macromolecular postsynaptic signalling complex at glutamatergic synapses. Currently, however, little is known about the in vivo function of SHANK3 at the synapse and how a disruption of Shank3 may contribute to ASDs. Here we demonstrate that genetic disruption of Shank3 in mice leads to compulsive/repetitive behaviour and impaired social interaction, resembling two of the cardinal features of ASDs. Biochemical, morphological and electrophysiological studies revealed synaptic dysfunction at corticostriatal synapses, part of the neural circuits strongly implicated as dysfunctional in ASDs. Our studies provide a synaptic and circuitry mechanism underlying Shank3 disruption and ASD-like behaviours. Shank3B 2/2 mice display repetitive grooming