Role of TRPC1 in the pathogenesis of depression induced by traumatic brain injury

Background: Traumatic brain injury (TBI) is one of the leading causes of mortality and disability, with many patients developing long-term sequelae. Depression is among the most common psychiatric complications following TBI, yet its underlying mechanisms remain unclear. Transient receptor potential canonical 1 (TRPC1) has been implicated in neurological disorders, but its role in post-TBI depression is not well understood. Methods: A controlled cortical impact (CCI) model was used to induce moderate TBI in mice. At 4 weeks post-injury, depressive-like behaviors were assessed using the tail suspension test (TST), forced swim test (FST), and sucrose preference test (SPT). Subsequently, reactive astrocytes and microglia were quantified, along with the expression of inflammatory cytokines, in the ipsilateral hippocampus. Synaptic function was also evaluated. Results: Behavioral tests revealed that TBI mice exhibited significant depressive- and anxiety-like behaviors at 4 weeks post-injury. Concurrently, TRPC1 expression was downregulated in the ipsilateral hippocampus, accompanied by reduced levels of synaptic-associated proteins, elevated pro-inflammatory cytokines, and increased reactive astrocytes and microglia. Further experiments demonstrated that TRPC1 overexpression attenuated neuroinflammation, restored synaptic function, and ameliorated depressive-like behaviors in TBI mice. Conclusion: This study suggests that TBI may trigger depression by downregulating TRPC1, thereby promoting neuroinflammation and synaptic dysfunction. Conversely, TRPC1 overexpression mitigates these effects, highlighting its potential as a therapeutic target for post-TBI depression.