Loss of TRPC5 causes obesity and postpartum depression. TRPC5, a brain-expressed cation channel, regulates instinctive behaviors such as feeding, arousal, social interaction, and maternal care. In humans, deletion of TRPC5 causes obesity, anxiety, autism, and postpartum depression. These phenotypes are recapitulated in mice with a human TRPC5 mutation. TRPC5 acts on hypothalamic Pomc and oxytocin (OXT) neurons to regulate these behaviors. Deletion of Trpc5 in OXT neurons in the paraventricular nucleus (PVH) causes obesity and postpartum depressive behavior, while overexpression reverses these effects. TRPC5 deficiency in humans is linked to obesity, anxiety, autism, and postpartum depression. Genetic studies show TRPC5 is the most strongly associated X-linked gene for BMI in the UK Biobank. TRPC5 deficiency in mice leads to increased food hoarding, anxiety, reduced sociability, and impaired maternal care. Restoration of TRPC5 in PVH OXT neurons improves these behaviors. TRPC5 plays a critical role in mediating innate behaviors essential for survival, including food seeking and maternal care. These findings highlight the importance of TRPC5 in human physiology and disease, with implications for the diagnosis and treatment of obesity, autism, and postpartum depression.Loss of TRPC5 causes obesity and postpartum depression. TRPC5, a brain-expressed cation channel, regulates instinctive behaviors such as feeding, arousal, social interaction, and maternal care. In humans, deletion of TRPC5 causes obesity, anxiety, autism, and postpartum depression. These phenotypes are recapitulated in mice with a human TRPC5 mutation. TRPC5 acts on hypothalamic Pomc and oxytocin (OXT) neurons to regulate these behaviors. Deletion of Trpc5 in OXT neurons in the paraventricular nucleus (PVH) causes obesity and postpartum depressive behavior, while overexpression reverses these effects. TRPC5 deficiency in humans is linked to obesity, anxiety, autism, and postpartum depression. Genetic studies show TRPC5 is the most strongly associated X-linked gene for BMI in the UK Biobank. TRPC5 deficiency in mice leads to increased food hoarding, anxiety, reduced sociability, and impaired maternal care. Restoration of TRPC5 in PVH OXT neurons improves these behaviors. TRPC5 plays a critical role in mediating innate behaviors essential for survival, including food seeking and maternal care. These findings highlight the importance of TRPC5 in human physiology and disease, with implications for the diagnosis and treatment of obesity, autism, and postpartum depression.