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

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. [Display omitted] • In humans, deletion of TRPC5 causes obesity, anxiety, autism, and postpartum depression • Male and female mice harboring a human TRPC5 mutation recapitulate these phenotypes • Effects are mediated by TRPC5 acting on hypothalamic Pomc and oxytocin neurons • Brain-expressed TRPC5 regulates instinctive behaviors essential for survival Disruption of TRPC5, a brain-expressed cation channel, causes obesity, maladaptive behavior, and postpartum depression in humans and mice. Acting on hypothalamic Pomc and oxytocin neurons, TRPC5 regulates instinctive behaviors such as feeding, arousal, social interaction, and maternal care, which are fundamental for survival. [ABSTRACT FROM AUTHOR]