Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice

Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striato-thalamo-cortical circuitry is implicated in OCD, although the underlying pathogenic mechanisms are unknown. SAP90/PSD95-associated protein 3 (SAPAP3; also known as DLGAP3) is a postsynaptic scaffolding protein at excitatory synapses that is highly expressed in the striatum. Here we show that mice with genetic deletion of Sapap3 exhibit increased anxiety and compulsive grooming behaviour leading to facial hair loss and skin lesions; both behaviours are alleviated by a selective serotonin reuptake inhibitor. Electrophysiological, structural and biochemical studies of Sapap3-mutant mice reveal defects in cortico-striatal synapses. Furthermore, lentiviral-mediated selective expression of Sapap3 in the striatum rescues the synaptic and behavioural defects of Sapap3-mutant mice. These findings demonstrate a critical role for SAPAP3 at cortico-striatal synapses and emphasize the importance of cortico-striatal circuitry in OCD-like behaviours. The underlying neurobiology of obsessive-compulsive disorder is largely unknown, although disruptions in corticostriatal circuits are suspected. For many medical conditions, mouse models provide a means of examining pathogenesis and drug testing. Surprisingly, that option is now available for obsessive-compulsive disorder too. Targeted deletion of SAPAP3, a postsynaptic scaffolding protein highly expressed in the striatum, yields mice with many of the behavioural characteristics of obsessive-compulsive disorder: they compulsively self-groom, display anxiety, and have abnormal corticostriatal physiology. The behavioural signs are alleviated by selective serotonin reuptake inhibitors, drugs used to treat obsessive-compulsive disorder. Targeted deletion of SAPAP3, a postsynaptic scaffolding protein expressed in the striatum, yields a behavioral phenotype with many characteristics of obsessive compulsive disorder (OCD). SAPAP3−/− mice compulsively overgroom themselves and are unusually anxious. Behavioral symptoms are alleviated by SSRIs, and both behaviour and physiological abnormalities are rescued by lentiviral-mediated expression of SAPAP3 in the striatum.