Memantine modulates TRPM3-associated glutamatergic signaling via vGLUT2 in a mouse model of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric disorder involving neuroinflammation, glutamatergic dysregulation, and altered calcium signaling. Our recent work identified transient receptor potential melastatin 3 (TRPM3) channels as key contributors to OCD pathogenesis via modulation of neuroinflammation and calcium homeostasis. Notably, calcium permeable N-Methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity is implicated in OCD through its impact on synaptic plasticity and neuronal survival in the medial prefrontal cortex (mPFC), a critical region for cognitive flexibility and inhibitory control, often impaired in OCD. Although both TRPM3 and NMDA receptors regulate calcium signaling associated inflammatory and synaptic pathways, their interaction remains unexplored. Memantine, a non-competitive NMDA receptor antagonist, has shown clinical benefit in treatment-resistant OCD. In this study, in-silico molecular docking analysis revealed a high binding affinity of memantine towards TRPM3. OCD-like behavior was induced in mice via chronic social isolation and restraint stress and measured by marble burying test, elevated plus maze and open field test. TRPM3 and vesicular glutamate transporter (vGLUT2) expression in the mPFC were assessed using immunohistochemistry, and IL-6 levels by ELISA. Treatment with memantine, primidone (TRPM3 inhibitor), or their combination significantly attenuated OCD-like behaviors, reduced TRPM3 and vGLUT2 immunoreactivity, and IL-6 concentrations. These findings support a novel TRPM3-vGLUT2-NMDA signaling axis in OCD, and suggest memantine and primidone as promising candidates for targeted, mechanism-based therapy.