Transient receptor potential melastatin 3-dependent disruption of hypothalamic paraventricular nucleus-medial prefrontal cortex serotonergic signaling promotes depressive-like behavior in ovariectomized rats.

Menopause is a natural biological process in women driven by estrogen deficiency and is associated with multiple postmenopausal physiological and behavioral changes. Notably, menopause increases the risk of depression. However, the precise neural mechanisms by which estrogen deficiency contributes to depressive phenotypes remain poorly understood. Estrogen deficiency has been reported to activate transient receptor potential melastatin 3 (TRPM3) channels and promote neuroinflammation by inducing microglial activation and upregulating proinflammatory cytokines. Although the paraventricular nucleus of hypothalamus (PVN) plays a central role in integrating the physiological response to stress, the role of TRPM3 channels in this region remains unexplored. We hypothesized that estrogen deficiency during menopause activates TRPM3 channels in the PVN, promoting neuroinflammation and disrupting medial prefrontal cortex (mPFC) function, thereby contributing to depressive-like phenotypes. Using a bilateral ovariectomy rat model, we demonstrated that estrogen loss induces robust depression-like behaviors, accompanied by increased TRPM3 expression and interleukin-1β levels in the PVN, as well as reduced dendritic complexity and serotonin levels in the mPFC. In the present study, retrograde 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) tracing confirmed direct PVN-mPFC connectivity, and immunofluorescence revealed coexpression of TRPM3 and the serotonin transporter in PVN neurons, implicating TRPM3 in serotonergic regulation. Notably, intraperitoneal administration of the TRPM3 inhibitor, naringenin reversed behavioral deficits, restored dendritic arborization in PVN, attenuated neuroinflammation, and normalized mPFC serotonin levels. These findings indicate that TRPM3-mediated PVN neuroinflammation disrupts mPFC serotonin signaling, contributing to menopause-associated depressive phenotypes and identifying TRPM3 as a potential therapeutic target. SIGNIFICANCE STATEMENT: This study identifies TRPM3 as a key mechanistic link between estrogen deficiency and depression during menopause. Current treatments, including hormone therapy and conventional antidepressants, often provide incomplete relief in menopausal depression, highlighting the need for more targeted strategies. This study shows that TRPM3 activation in the PVN drives neuroinflammation, disrupts mPFC serotonin signaling, and induces depression-like behaviors. Importantly, TRPM3 inhibition reverses these effects, suggesting its therapeutic potential and offering a novel target for menopause-associated depression.