Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric condition with a significant genetic basis.
• The SLC1A1 gene, encoding the neuronal glutamate transporter EAAT3, is implicated in OCD.
• Previous mouse models lacking EAAT3 did not exhibit OCD-related behaviors.

Purpose of the Study:

• To investigate the behavioral and synaptic effects of increased EAAT3 expression.
• To develop a novel transgenic mouse model for studying OCD.

Main Methods:

• Generated a transgenic mouse model (EAAT3^glo) for conditional EAAT3 overexpression.
• Administered fluoxetine and clomipramine to assess behavioral restoration.
• Performed electrophysiological and biochemical analyses of corticostriatal synapses.

Main Results:

• EAAT3 overexpression in mice (EAAT3^glo/CMKII) led to increased anxiety-like and repetitive behaviors.
• Chronic treatment with fluoxetine or clomipramine reversed these behaviors.
• Observed alterations in NMDA receptor composition and synaptic plasticity in affected mice.

Conclusions:

• Increased EAAT3 function contributes to OCD pathogenesis.
• The findings support the glutamatergic hypothesis of OCD.
• This EAAT3 overexpression model offers a platform for developing new OCD therapeutics.