Forebrain EAAT3 Overexpression Increases Susceptibility to Amphetamine-Induced Repetitive Behaviors

• Published in: eNeuro 2024-04, Vol.11 (4), p.ENEURO.0090-24.2024
• Main Authors: Kopelman, Jared M, Chohan, Muhammad O, Hsu, Alex I, Yttri, Eric A, Veenstra-VanderWeele, Jeremy, Ahmari, Susanne E
• Format: Article
• Language: English
• Subjects: Amphetamine - pharmacology; Animals; Corpus Striatum - metabolism; Disease Models, Animal; Excitatory Amino Acid Transporter 3 - genetics; Excitatory Amino Acid Transporter 3 - metabolism; Mice; Obsessive-Compulsive Disorder - chemically induced; Obsessive-Compulsive Disorder - genetics; Obsessive-Compulsive Disorder - metabolism
• ISSN: 2373-2822; 2373-2822
• DOI: 10.1523/ENEURO.0090-24.2024

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive obsessive thoughts and compulsive behaviors. Multiple studies have shown the association of polymorphisms in the gene with OCD. The most common of these OCD-associated polymorphisms increases the 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 in forebrain neurons. The 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 -overexpressing (OE) mice, but -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 -OE mice, relative to controls. Lastly, we found that the differences in striatal cFos expression in -OE mice were driven by cFos expression specifically in D1 neurons, as -OE mice had increased cFos in D1 ventral medial striatal neurons, implicating this region in the exaggerated behavioral response to amphetamine in -OE mice.