Activity- and Sleep-Dependent Regulation of Tonic Inhibition by Shisa7

Tonic inhibition mediated by extrasynaptic GABAA receptors (GABAARs) in the brain serves as a powerful modulator of neuronal excitability, and contributes to important processes involved in sensory processing, behavior and cognition. However, the molecular mechanisms regulating tonic inhibition remain poorly understood. Here we report that Shisa7 is critical for the regulation of tonic inhibition in hippocampal neurons. In Shisa7 knockout neurons, α5-GABAAR mediated tonic currents were significantly reduced. Mechanistically, Shisa7 is crucial for α5-GABAAR exocytosis. Additionally, Shisa7-dependent regulation of tonic inhibition requires protein kinase A (PKA) that phosphorylates Shisa7 S405. Importantly, tonic inhibition undergoes activity-dependent bidirectional regulation, and Shisa7 is required for homeostatic potentiation of tonic inhibition. Furthermore, tonic inhibition oscillates during the daily sleep-wake cycle, and sleep-dependent regulation of tonic inhibition requires phosphorylation of Shisa7 S405. Together, these data demonstrate an intricate signaling mechanism regulating tonic inhibition and reveal an unappreciated molecular link between sleep and tonic inhibition.