GLUT4 plasma translocation in lateral septum GABAergic neurons supports neuronal activation and social familiarity.

Social interaction regulates neuronal excitability and behavior, and the lateral septum (LS) plays an important role in social behavior. However, the molecular mechanisms that support LS-dependent social responses remain unclear. Here, we show that neuronal activity-driven glucose transporter 4 (GLUT4) plasma translocation in LS GABAergic neurons supports social familiarity. Neuronal activation triggers CaMKIIα-mediated phosphorylation of GLUT4 at Ser243 and Ser254, which enhances Rab10 binding, GLUT4 surface insertion, and glucose uptake. A cell-permeable TAT-GLUT4(2D) peptide disrupts GLUT4-Rab10 binding, blocks activity-dependent GLUT4 translocation, and impairs social familiarity. LS GLUT4 knockdown disrupts social novelty preference, and this deficit is rescued by wild-type GLUT4 but not trafficking- or transport-deficient mutants. In 5xFAD mice, GLUT4 plasma translocation is reduced during social novelty preference. Selective expression of plasma-localized GLUT4 in LS GABAergic neurons restores neuronal activation and social familiarity impairments, identifying GLUT4 trafficking as a potential target for Alzheimer's disease-related social impairments.