Novel molecular insights into the role of CRH type 1 receptor in the pathophysiology of depression

Depression is a debilitating mental health condition marked by persistent sadness, loss of pleasure, and suicidal thoughts. The continuous rise in cases of depression signifies the lack of efficient treatment options and therapeutic targets. Corticotropin-releasing hormone (CRH) is a member of the neuropeptide family and is a robust component of the hypothalamic-pituitary-adrenal (HPA) axis dysregulation in depression. Several studies have highlighted the significant role of corticotropin-releasing hormone receptor type 1 (CRHR1) in the development of depressive symptoms. CRHR1, a member of the G-protein-coupled receptor (GPCR) superfamily, is widelydistributed throughout the mammalian brain and plays a dynamic role in brain function, notably interacting with neurotransmitters such as glutamate, serotonin, and dopamine, which are crucial in brain functioning. Furthermore, genetic alterations such as polymorphism and epigenetic modification in the Crhr1 gene increase the risk of depression. Additionally, we discussed the role of CRHR1 in novel mechanisms such as synaptic plasticity, neuroinflammation, autophagy, and gut dysbiosis, and its implications in depression. This article compiles and discusses emerging evidence regarding the role of CRHR1 in these mechanisms, which are central to the pathophysiology of depression. Evidence suggests that the CRHR1 may play an even more crucial role than CRH in the manifestation of depressive symptoms; we also examined this aspect briefly. In conclusion, these findings underscore the importance of CRHR1 in the neurobiological mechanisms underlying depression, suggesting that targeting this receptor could be a potential therapeutic avenue for treating mood disorders.