Genetic linkage and association studies in obsessive-compulsive disorder (OCD) implicate SLC1A1 (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.
Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in ( i) locomotor activity, ( ii) stereotypy, and ( iii) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D 1 receptor binding in the dorsal striatum of Slc1a1-STOP mice. Slc1a1-STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of Slc1a1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in Slc1a1-STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.