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• W2615511331 abstract "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 D1 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." @default.
• W2615511331 created "2017-05-26" @default.
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• W2615511331 date "2017-05-15" @default.
• W2615511331 modified "2023-10-14" @default.
• W2615511331 title "OCD candidate gene <i>SLC1A1</i> /EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior" @default.
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• W2615511331 doi "https://doi.org/10.1073/pnas.1701736114" @default.
• W2615511331 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5465902" @default.
• W2615511331 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/28507136" @default.
• W2615511331 hasPublicationYear "2017" @default.
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