Shank3 mutant mice exhibit autistic-like behaviors and striatal dysfunction. The study, conducted by researchers from Duke University Medical Center and other institutions, focuses on the role of Shank3, a postsynaptic protein, in autism spectrum disorders (ASDs). Shank3 disruption is associated with 22q13 deletion syndrome and other non-syndromic ASDs. The researchers generated two types of Shank3 mutant mice: *Shank3A* and *Shank3B*. *Shank3B*−/− mice displayed self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological, and biochemical analyses revealed defects at striatal synapses and cortico-striatal circuits in these mutant mice. The findings establish a critical role for Shank3 in normal neuronal connectivity development and link its disruption to autistic-like behaviors in mice. The study provides insights into the synaptic and circuitry mechanisms underlying ASDs.Shank3 mutant mice exhibit autistic-like behaviors and striatal dysfunction. The study, conducted by researchers from Duke University Medical Center and other institutions, focuses on the role of Shank3, a postsynaptic protein, in autism spectrum disorders (ASDs). Shank3 disruption is associated with 22q13 deletion syndrome and other non-syndromic ASDs. The researchers generated two types of Shank3 mutant mice: *Shank3A* and *Shank3B*. *Shank3B*−/− mice displayed self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological, and biochemical analyses revealed defects at striatal synapses and cortico-striatal circuits in these mutant mice. The findings establish a critical role for Shank3 in normal neuronal connectivity development and link its disruption to autistic-like behaviors in mice. The study provides insights into the synaptic and circuitry mechanisms underlying ASDs.