Trpc5-activated neural circuits and maternal behavior - PROJECT SUMMARY Parental behavior is the hallmark feature of all mammals, and is critical to the health of both parents and offspring. In the majority of mammals, since only the female can lactate, it is the mother who provides maternal care and protection of the young. Inadequate maternal care can adversely influence the development of the offspring and impair their health in adulthood. However, the neurobiological mechanisms for the regulation of maternal behavior remain to be fully understood. In women who exhibit impaired bonding with their infants, we identified several loss-of-function mutations in the TRPC5 gene, which encodes the TRPC5 ion channel, a transient receptor potential channel that conducts calcium inward currents. We used the CRISPR-Cas9 approach to generate a knock-in mouse line that mimics one such human mutation, Trpc5K34del, and found that this mutation causes severe impairments in a wide range of maternal behaviors in mouse dams, including ignoring pups, reduced nursing/crouching, inefficient retrieval, disrupting nests, and impaired prolactin release upon suckling. These findings demonstrate that intact Trpc5 function is required for normal maternal behavior, but the neurobiological mechanisms for its effect remain unclear. One objective is to test a hypothesis that Trpc5 maintains maternal behavior via activating oxytocin neurons in the paraventricular nucleus of the hypothalamus, which have been implicated in maternal behavior and mother-infant bonding. The second objective is to test whether Trpc5 acts upon dopamine neurons in the substantia nigra to provide a redundant or complementary mechanism to regulate maternal behavior. Finally, we will evaluate whether a Trpc5 activator can ameliorate impaired maternal behavior in wild-type dams induced by psychological stress. Our work, combining human genetic and mouse genetic experiments, has provided evidence to identify a novel molecular basis underlying normal maternal behavior. As a logical extension of this initial and exciting discovery, we will continue to unravel the neurobiological mechanisms by which Trpc5 maintains normal maternal behavior during the postpartum period and will provide pre-clinical evidence to identify Trpc5 as a potential target improve maternal care.
