eNeuro. 2024 Mar 21:ENEURO.0090-24.2024. doi: 10.1523/ENEURO.0090-24.2024. Online ahead of print.

ABSTRACT

Obsessive Compulsive Disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive obsessive thoughts and compulsive behaviors. Multiple studies have shown association of polymorphisms in the SLC1A1 gene with OCD. The most common of these OCD-associated polymorphisms increases expression of the encoded protein, Excitatory Amino Acid Transporter 3 (EAAT3), a neuronal glutamate transporter. Previous work has shown that increased EAAT3 expression results in OCD-relevant behavioral phenotypes in rodent models. In this study, we created a novel mouse model with targeted, reversible overexpression of Slc1a1 in forebrain neurons. These mice do not have a baseline difference in repetitive behavior but show increased hyperlocomotion following a low dose of amphetamine (3 mg/kg) and increased stereotypy following a high dose of amphetamine (8 mg/kg). We next characterized the effect of amphetamine on striatal cFos response and found that amphetamine increased cFos throughout the striatum in both control and Slc1a1-overexpressing (OE) mice, but Slc1a1-OE mice had increased cFos expression in the ventral striatum relative to controls. We used an unbiased machine classifier to robustly characterize the behavioral response to different doses of amphetamine and found a unique response to amphetamine in Slc1a1-OE mice, relative to controls. Lastly, we found that the differences in striatal cFos expression in Slc1a1-OE mice were driven by cFos expression specifically in D1 neurons, as Slc1a1-OE mice had increased cFos in D1 ventral medial striatal neurons, implicating this region in the exaggerated behavioral response to amphetamine in Slc1a1-OE mice.Significance statement Obsessive compulsive disorder is a debilitating psychiatric disorder with inadequate treatment options. The gene SLC1A1 has been associated with OCD in humans, and studies in rodents have shown alterations in OCD-relevant behavior and neural activity in mice with increased Slc1a1 expression. We created a novel mouse model with reversible forebrain overexpression of Slc1a1 and found that these mice show increased behavioral response to amphetamine. Using an unbiased machine classifier we found differences in clusters of amphetamine-induced behaviors in Slc1a1-overexpressing mice. In addition, Slc1a1-overexpressing mice showed increased neuronal activation in D1-expressing cells in ventromedial striatum following amphetamine administration. These results provide information about the role of Slc1a1 in repetitive behaviors and may contribute to novel treatments going forward.

PMID:38514191 | DOI:10.1523/ENEURO.0090-24.2024