Shank3 mutant mice exhibit autistic-like behaviors and striatal dysfunction. The study shows that mice with Shank3 gene deletions display self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological, and biochemical analyses reveal defects in striatal synapses and cortico-striatal circuits in Shank3 mutant mice. The findings demonstrate a critical role for Shank3 in normal neuronal connectivity development and establish causality between Shank3 gene disruption and the emergence of autistic-like behaviors in mice. Shank3 is a postsynaptic protein whose disruption is thought to cause 22q13 deletion syndrome and other non-syndromic ASDs. Shank3B^-/- mice display repetitive grooming and self-injurious behavior, along with social interaction deficits. These mice also show altered PSD composition in the striatum, morphological defects in medium spiny neurons, and striatal hypertrophy. Electrophysiological studies reveal impaired synaptic function in cortico-striatal circuits, indicating a postsynaptic impairment in synaptic function and/or reduced number of functional synapses. The study also shows that Shank3B^-/- mice have normal hippocampal-dependent learning and memory, suggesting that the observed behavioral and synaptic defects are specific to discrete brain regions and not part of an overall CNS dysfunction. The study highlights the critical in vivo role of Shank3 in the normal development of medium spiny neurons and striatal glutamatergic synapses. The findings support the hypothesis that repetitive behaviors in OCD and ASD may share a common circuitry mechanism. The study provides a synaptic and circuitry mechanism underlying Shank3 disruption and ASD-like behaviors.Shank3 mutant mice exhibit autistic-like behaviors and striatal dysfunction. The study shows that mice with Shank3 gene deletions display self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological, and biochemical analyses reveal defects in striatal synapses and cortico-striatal circuits in Shank3 mutant mice. The findings demonstrate a critical role for Shank3 in normal neuronal connectivity development and establish causality between Shank3 gene disruption and the emergence of autistic-like behaviors in mice. Shank3 is a postsynaptic protein whose disruption is thought to cause 22q13 deletion syndrome and other non-syndromic ASDs. Shank3B^-/- mice display repetitive grooming and self-injurious behavior, along with social interaction deficits. These mice also show altered PSD composition in the striatum, morphological defects in medium spiny neurons, and striatal hypertrophy. Electrophysiological studies reveal impaired synaptic function in cortico-striatal circuits, indicating a postsynaptic impairment in synaptic function and/or reduced number of functional synapses. The study also shows that Shank3B^-/- mice have normal hippocampal-dependent learning and memory, suggesting that the observed behavioral and synaptic defects are specific to discrete brain regions and not part of an overall CNS dysfunction. The study highlights the critical in vivo role of Shank3 in the normal development of medium spiny neurons and striatal glutamatergic synapses. The findings support the hypothesis that repetitive behaviors in OCD and ASD may share a common circuitry mechanism. The study provides a synaptic and circuitry mechanism underlying Shank3 disruption and ASD-like behaviors.