Functional Characterization of a glutamate transporter point mutation associated with Obsessive-Compulsive Disorder.

Wednesday, November 06, 2013 — Poster Session I
4:00 p.m. – 6:00 p.m.	FAES Academic Center (Upper-Level Terrace)	NIMH	NEURO-36

Authors

D Torres-Salazar
PR Moya
SG Amara

Abstract

Obsessive-Compulsive Disorder (OCD) is a common incapacitating neuropsychiatric disorder. Increasing evidence suggests that glutamatergic neurotransmission contribute to the pathogenesis of OCD. Several linkage studies have identified a glutamate transporter gene, SLC1A1/EAAC1/EAAT3, potentially involved in OCD. Recently, a rare SLC1A1 variant, Thr164Ala, has been detected in a population of OCD patients. Heterologously expressed proteins bearing this mutation showed a reduced transport activity. Here we investigate whether such a reduced activity is due to an impairment of the transport mechanism or an alteration in trafficking to the plasma membrane. To address this question, we expressed wildtype and mutant hEAAT3 transporters in Xenopus oocytes and measured substrate transport and anion currents mediated by hEAAT3. We consistently observe a 50% reduction of the transport activity of the T164A hEAAT3. Preliminary data suggest that this reduction in transport activity may arise from a decrease in the efficiency of trafficking of mutant carriers to the cell surface. Because this mutation has a significant effect on EAAT3 function, these studies provide a basis for further work to examine its impact on glutamatergic neurotransmission in critical circuits linked to OCD and are a step forward toward understanding how glutamate clearance contributes to the molecular basis of OCD.