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Significance Genetic linkage and association studies in obsessive-compulsive disorder (OCD) implicateSLC1A1 (encoding the neuronal glutamate transporter excitatory amino acid transporter 3, EAAT3), and neuroimaging studies demonstrate abnormal basal ganglia circuit function in OCD. However, no previous studies have investigated the role of EAAT3 in these circuits or tested its impact on repetitive behavior. Using a combined genetic and pharmacological challenge approach, we have demonstrated that ablated expression of EAAT3 diminishes basal ganglia-mediated repetitive behavior in mice. Targeted rescue of midbrain expression points to an impact of EAAT3 on dopaminergic neuron function, suggesting a model for synthesizing glutamate and dopamine effects on stereotypic behavior. These findings provide evidence that EAAT3 impacts basal ganglia-dependent repetitive behavior and suggest a potential target for drug development.

OCD candidate gene SLC1A1 /EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior