Loss of transient receptor potential channel 5 causes obesity and postpartum depression

This is the final version. Available on open access from Elsevier via the DOI in this recordData and code availability: Data. GOOS WES data are accessible from the European Genome-phenome Archive-EGA:EGAS00001000124. Access to the UK Biobank genotype and phenotype data are open to all approved health researchers, accessible through https://www.ukbiobank.ac.uk. Requests for de-identified data relating to clinical studies may be addressed to the corresponding author (I.S.F.) Limitations on clinical data are designed to protect and respect patient and participant confidentiality.Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care