# Investigation of EAAT3 in OCD Pathophysiology

> **NIH NIH R01** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2020 · $525,438

## Abstract

PROJECT SUMMARY
Obsessive-compulsive disorder (OCD) is one of the most disabling, chronic psychiatric disorders, with a
lifetime prevalence of 2-3%. Emerging findings point to a significant role for basal ganglia circuits in OCD.
Despite this, our understanding of the molecular pathophysiology of OCD remains inadequate, and our
treatment options leave most patients with continued impairment. The best-replicated genetic finding in OCD is
association with SLC1A1, encoding the neuronal glutamate, aspartate, and cysteine transporter
EAAT3/EAAC1. However, the impact of this gene on the normal and abnormal functioning of OCD-related
circuits is unknown. To fill this knowledge gap, we developed a STOP-TetO knock-in mouse line that allows us
to flexibly manipulate Slc1a1 expression. Using dopamine agonists as a probe, we found that EAAT3 loss
decreases basal ganglia-mediated repetitive, stereotyped behavior. Our convergent data support the
hypothesis that increased EAAT3 function plays a role in OCD pathology and that decreasing EAAT3 activity
may serve as a novel treatment option. Little is known, however, about EAAT3's molecular and functional
impact in the basal ganglia. Elsewhere in the brain, EAAT3-mediated transport decreases neurotransmission
at perisynaptic glutamate receptors and provides substrate for GABA and glutathione synthesis, but it is
unclear which of these functions is important in basal ganglia circuits, and whether EAAT3's impact on
dopaminergic neurotransmission is pre- or post-synaptic. Using our flexible mouse model and previously
established OCD optogenetic and transgenic mouse models, this R01 will 1) examine effects of EAAT3
ablation and targeted rescue on basal ganglia function and repetitive behavior, and 2) determine if EAAT3
ablation leads to symptom resolution in phenotypically-similar but etiologically-independent mouse models of
OCD with abnormal basal ganglia signaling. These data could be leveraged to demonstrate a clear treatment
target that motivates development of promising EAAT3 inhibitor lead compounds.

## Key facts

- **NIH application ID:** 9919631
- **Project number:** 5R01MH114296-04
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** Susanne Elizabeth Ahmari
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $525,438
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9919631

## Citation

> US National Institutes of Health, RePORTER application 9919631, Investigation of EAAT3 in OCD Pathophysiology (5R01MH114296-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9919631. Licensed CC0.

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