1524-P: Selective Deletion of Nav1.7 in Cerebellar Purkinje Neurons Prevents Diet-Induced Obesity by Promoting Voluntary Locomotion Free

The pacemaker activity of cerebellum Purkinje neurons is well-known to be essential in multiple physiological functions, including voluntary locomotion, balance, aggressive behavior, and cognitive behavior. However, the specific ionic mechanism of Purkinje neurons in regulating voluntary locomotion is still unclear. To this end, we ex vivo electrophysiologically recorded the activity changes of Purkinje neurons after wheel running by using Pcp2-Cre/Rosa26-LTL-tdTOMATO reporter mice with tdTOMATO selectively expressed in Purkinje neurons. We found that the Purkinje neural activity was reduced by wheel running, associated with decreases in voltage-gated sodium current and expression of the voltage-gated sodium ion channel Nav1.7 (Scn9a), suggesting a potential role of Nav1.7-mediated sodium current. To test whether Nav1.7 is required for the activity dynamics of Purkinje neurons induced by voluntary wheel running and subsequent beneficial metabolic effects, we crossed Scn9a^flox/flox mice with Pcp2-Cre mice to generate a mouse model with Nav1.7 selectively deleted from Purkinje neurons (Pcp2-Cre/Scn9a^flox/flox, Nav1.7-KO^Pcp2). Nav1.7-KO^Pcp2 significantly decreased Purkinje neural dynamics, mimicking wheel running-induced neural activity reduction. Nav1.7-KO^Pcp2 mice also significantly increased voluntary locomotion compared to the control littermates. Further, Nav1.7-KO^Pcp2 mice showed decreased body weight gain, reduced blood glucose, and improved insulin sensitivity when fed a high-fat diet (HFD). These beneficial metabolic effects were associated with increased running activity but not food intake.

In summary, these findings provide evidence to support the vital role of the Nav1.7 ion channel expressed by Purkinje neurons in the beneficial metabolic effects of voluntary locomotion activity.