Neel Shah

 Introduction. Obsessive-Compulsive Disorder (OCD) is characterized by having recurrent unwanted thoughts and fears (obsessions) that lead to organized and ritualistic behaviors (compulsions)^1-5. Even with a prevalence of 2%-3% in the worldwide population, up to 40% of patients report no response to first-line treatments of selective serotonin reuptake inhibitors (SSRIs) and/or cognitive-behavioral therapy^1,2. Studies have shown glutamate dysfunction in these patients as increases in glutamatergic activity in the striatum, orbitofrontal cortex, and cerebrospinal fluid were measured². The SLC1A1 gene, which has the strongest candidate gene association for OCD, codes for the high-affinity neuronal glutamate transporter EAAT3^2,5. This transporter, which is found on post-synaptic and extra-synaptic membranes of the neurons, is important for buffering extracellular glutamate concentration below neurotoxic levels around NMDA receptors^5,6. This indicates that EAAT3 dysfunction could impact glutamate concentrations in different regions of the brain as seen in patients with OCD⁵. Methods. A transgenic mouse model (EAAT3^glo) was utilized to attain Cre-dependent EAAT3 overexpression. The mice with EAAT3 overexpression driven by CaMKIIα-promoter (EAAT3^glo/CMKII) did a series of challenges such as the open-field test, light-dark box test, marble burying test, and grooming analysis that measured their behaviors. Whole-cell voltage-clamp recordings were obtained from the dorsal striatum in these mice. The electrophysiological recordings of corticostriatal synapses were utilized to analyze NMDAR/AMPAR ratios and isolated NMDAR-EPSCs. Ro25-6981 (500nM), a selective blocker of GluN2B-containing NMDARs, was utilized to demonstrate a potential change in NMDAR subunit composition. Results.  The EAAT3^glo/CMKII mice had increased anxiety-like and repetitive behaviors such as increased grooming time, buried more marbles, and longer latency to enter lit chamber compared to the control⁶. The mice with EAAT3 overexpression showed slower decay kinetics of NMDAR-EPSCs⁶. Compared to the control (EAAT3^glo) mice, the NMDAR-EPSCs in EAAT3^glo/CMKII mice were more sensitive to Ro25-6981⁶. Therefore, the mice with EAAT3 overexpression had altered NMDA receptor subunit composition and NMDA-dependent synaptic plasticity, and this is linked to OCD-like behavioral deficits⁶. Conclusions. These results indicate EAAT3 overexpression increased basal ganglia mediated behaviors as seen in OCD patients⁶. It was found that EAAT3 played a role in the regulation of the NMDA receptor^6,7. In clinical trials, glutamate-modulating drugs that worked on the NMDA receptor, such as memantine and amantadine, have had promising results in refractory OCD cases⁸. Although more research is needed to demonstrate the specific mechanisms that link EAAT3 and NMDA receptors, the mice models have provided valuable insight into the key relationship of EAAT3 in OCD pathogenesis.

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5. Escobar, A.P., Wendland. JR., Chavez. A.E., Moya. P.R. The Neuronal Glutamate Transporter EAAT3 in Obsessive-Compulsive Disorder. Front Pharmacol., 2019;10:1362. doi: 3389/fphar.2019.01362
6. Delgado-Acevedo, C., Estay, S.F., Radke, A. et al.Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression.  44, 1163–1173 (2019). https://doi.org/10.1038/s41386-018-0302-7
7. Zike ID, Chohan MO, Kopelman JM, et al. OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior. Proc Natl Acad Sci U S A. 2017;114(22):5719–5724. doi:10.1073/pnas.1701736114
8. Modarresi, A., Sayyah, M., Razooghi, S., Eslami, K., Javadi, M., Kouti, L. Memantine Augmentation Improves Symptoms in Serotonin Reuptake Inhibitor-Refractory Obsessive-Compulsive Disorder: A Randomized Controlled Trial. Pharmacopsychiatry 2018; 51: 263–269. https://doi.org/10.1055/s-0043-120268