9270 Human loss-of-function variants in the TRPC5 associated with Postpartum Depression

Disclosure: Y. Li: None. I.S. Farooqi: None. Y. Xu: None. Postpartum depression is a serious psychiatric disorder that is understudied and underdiagnosed. Postpartum depression, the most common complication of childbirth negatively impacts the mother, with suicide accounting for approximately 20% of postpartum deaths. Further, postpartum depression also has adverse effects on infant behavioral, emotional, and cognitive development. However, the neurobiological mechanisms underlying postpartum depression remain to be comprehensively elucidated. Transient receptor potential channel 5 (TRPC5/Trpc5), an ion channel that conducts calcium inward currents, as a critical regulator of many behaviors. Here, we found that microdeletions on chromosome Xq23 disrupting TRPC5 gene in humans and identified seven rare TRPC5 variants in mothers who exhibited postpartum depression and reduced bonding with their infants. Heterozygous females with TRPC5 deletions had postpartum depression and anxiety after delivery. We then generated a knock-in mouse model of a human severe loss-of-function mutation, K34del (Trpc5K34del). Our study showed that Trpc5K34del/+ heterozygous dams abandoned their pups after delivery. The Trpc5K34del/+ dams also showed inefficient retrieval and increased the time to retrieve pups, which is associated with abnormal pup care. Importantly, Trpc5K34del/+ dams exhibited severe depression-like and anxiety-like behaviors during the postpartum period. Oxytocin (OXT), a polypeptide comprised of 9 amino acids, is primarily synthesized by neurons in the paraventricular nucleus of the hypothalamus (PVH) and the supraoptic nucleus (SON). We found that endogenous Trpc5 protein is abundantly expressed by OXT neurons in PVH but not by SON. Further, the Trpc5K34del/+ dams reduced OXT expression in the PVH but does not affect OXT expression in the SON. Deletion of Trpc5 in OXTPVH neurons recapitulated phenotypes in Trpc5K34del/+ dams, including inefficient retrieval, abnormal pup care, depression-like and anxiety-like behaviors during the postpartum period. We then bilaterally injected AAV-DIO-Trpc5 into the PVH of virgin female Trpc5K34del/+/OXT-Cre mice to result in restoration of Trpc5 only in OXTPVH neurons in these mutant mice. Restoration of Trpc5 in OXTPVH neurons in Trpc5K34del/+/OXT-Cre mutant mice significantly improved pup retrieval behavior and indices of maternal care. After weaning, Trpc5K34del/+/OXT-Cre dams with Trpc5 restoration in OXTPVH neurons showed reduced depression-like and anxiety-like behaviors. Our study indicates that the postpartum depression and impaired maternal behavior of Trpc5 deficient female mice are mediated by impaired function of OXTPVH neurons. This revelation not only offers crucial insights into the pathogenesis of postpartum depression but also provides a foundation for potential therapeutic interventions. Presentation: 6/2/2024