TY - JOUR T1 - Distinct regulation of tonic GABAergic inhibition by NMDA receptor subtypes JF - bioRxiv DO - 10.1101/2021.05.30.446187 SP - 2021.05.30.446187 AU - Kunwei Wu AU - David Castellano AU - Qingjun Tian AU - Wei Lu Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/05/30/2021.05.30.446187.abstract N2 - Tonic inhibition mediated by extrasynaptic γ-aminobutyric acid type A receptors (GABAARs) play important roles in the regulation of various brain functions. However, the regulatory mechanisms for tonic inhibition remain largely unknown. Here we report distinct actions of GluN2A- and GluN2B-containing subtypes of NMDA receptors (NMDARs) on tonic inhibition in hippocampal neurons. Mechanistically, GluN2A- and GluN2B-containing NMDARs play differential roles in α5-GABAAR internalization. Additionally, GluN2A-, but not GluN2B-, containing receptors are required for the homeostatic potentiation of tonic inhibition. In an acute seizure model induced by kainic acid, tonic inhibition is decreased during acute seizures, while it is increased 24 h later, and these alterations are dependent on the distinct GluN2-containing NMDARs. Collectively, these data reveal a critical link between NMDARs and extrasynaptic GABAARs in both physiological and pathological conditions.Competing Interest StatementThe authors have declared no competing interest. ER -