Therapeutic effects of TRPC4/5 antagonism in a rat model of bipolar disorder

Bipolar disorder, a chronic neuropsychiatric condition, is characterized by alternating episodes of mania and depression. Although acute manic episodes have become increasingly manageable with the advent of third-generation neuroleptics, the primary therapeutic challenge remains the prevention of recurrences and the effective management of often refractory depressive phases. Emerging evidence implicates transient receptor potential (TRP) channels in mood regulation through their roles in calcium signaling, synaptic plasticity, and neuroinflammation. Among these, TRPC5 has gained attention as a potential neuromodulatory target; however, the contribution of TRPC4/5 channels to bipolar disorder-related pathophysiology remains unclear. In the present study, we investigated the effects of pharmacological inhibition of TRPC4/5 channels using ML204 in an ouabain-induced rat model of bipolar disorder. Behavioral outcomes were assessed using the open field and sucrose preference tests, and molecular alterations in the hippocampus were evaluated by Western blotting and immunofluorescence. Intracerebroventricular administration of ouabain induced a bipolar-like phenotype characterized by hyperlocomotion, altered exploratory behavior, and anhedonia-like responses. Treatment with ML204 attenuated these behavioral alterations, with effects comparable to those of lithium. At the molecular level, ouabain disrupted the expression of proteins associated with synaptic function, neurotrophic signaling, oxidative stress, and glial activation, including GSK3β, BDNF, TrkB, PSD-95, synaptophysin, GFAP, and HO-1. ML204 treatment partially normalize these changes and reduced astrocytic activation. Collectively, these findings indicate that pharmacological inhibition of TRPC4/5 channels improves behavioral and molecular alterations observed in this experimental model. Importantly, given the lack of channel subtype specifity of ML204, the relative contribution of TRPC4/5 compared with other TRPC channels cannot be determined. Further studies using more selective approaches are required to clarify the channel-specific mechanisms underlying these effects.