Shisa7 phosphorylation regulates GABAergic transmission and neurodevelopmental behaviors

GABA-A receptors (GABA_ARs) are crucial for development and function of the brain. Altered GABAergic transmission is hypothesized to be involved in neurodevelopmental disorders. Recently, we identified Shisa7 as a GABA_AR auxiliary subunit that modulates GABA_AR trafficking and GABAergic transmission. However, the underlying molecular mechanisms remain elusive. Here we generated a knock-in (KI) mouse line that is phospho-deficient at a phosphorylation site in Shisa7 (S405) and combined with electrophysiology, imaging and behavioral assays to illustrate the role of this site in GABAergic transmission and plasticity as well as behaviors. We found that expression of phospho-deficient mutants diminished α2-GABA_AR trafficking in heterologous cells. Additionally, α1/α2/α5-GABA_AR surface expression and GABAergic inhibition were decreased in hippocampal neurons in KI mice. Moreover, chemically induced inhibitory long-term potentiation was abolished in KI mice. Lastly, KI mice exhibited hyperactivity, increased grooming and impaired sleep homeostasis. Collectively, our study reveals a phosphorylation site critical for Shisa7-dependent GABA_ARs trafficking which contributes to behavioral endophenotypes displayed in neurodevelopmental disorders.