Inhibition of TRPM3 channels in the medial prefrontal cortex mitigates OCD symptoms following traumatic brain injury

Abstract

Although tumor necrosis factor-alpha (TNF-α) plays an important role in the development of obsessive-compulsive disorder (OCD), the pathogenesis remains unclear. Since transient receptor potential melastatin 3 (TRPM3) channels are activated during inflammatory conditions, crosstalk with TNF-α in the progression of OCD has not been investigated yet. We hypothesize that mild traumatic brain injury (mTBI) stimulates TRPM3 channels, thereby enhancing the level of TNF-α in the medial prefrontal cortex (mPFC), a key brain region implicated in OCD pathogenesis. The closed-head weight-drop method was used for mTBI-induced OCD in mice, and neurological assessment was carried out using rotarod and beam-walk tests. Marble-burying test, open-field test, dark-light emergence test, and nest-building behavior test were performed to examine OCD-like symptoms. The mPFC was isolated, and the TNF-α level and TRPM3 immunoreactivity were estimated using ELISA and immunohistochemistry techniques. Additionally, Golgi-Cox staining and HPLC were performed to quantify dendritic arbor and serotonin content. To validate our hypothesis, mTBI mice were treated with a selective TRPM3 inhibitor naringenin (50 mg/kg) via intraperitoneal route, and all the above parameters were screened. Marble-burying and nest-building behaviors were increased in mTBI mice. However, exploratory behavior and time spend in the light chamber were significantly reduced. Moreover, mTBI increases TNF-α concentration and TRPM3 immunoreactivity, while decreasing dendritic arbor and serotonin content. Notably, naringenin treatment reversed these behavioral, biochemical, and molecular abnormalities. Naringenin may inhibit TRPM3-mediated TNF-α production and serotonin transmission, thereby suppressing OCD symptoms. Thus, we propose a novel therapeutic approach for treating OCD associated with traumatic brain injury.

Keywords: OCD; Serotonin; TNF-α; TRPM3 channels; mPFC.