Neuronal activity-induced GLUT3 plasma translocation supports energy demands for memory acquisition.

Glucose transporter 3 (GLUT3) is crucial for glucose uptake in neurons and rapidly translocates to the plasma membrane in response to neural activity. However, the precise molecular mechanisms and physiological roles of this translocation remain elusive, hindering our understanding of how glucose metabolism supports brain function. This study found that PKCε phosphorylates Thr232 and Ser246 of GLUT3 upon neuronal activation, enhancing its binding to KLC1 and promoting GLUT3 plasma membrane insertion. To investigate the function of GLUT3 plasma translocation, we developed a peptide, TAT-GLUT3(2D), which disrupts GLUT3-KLC1 binding and blocks activity-dependent translocation of GLUT3. By utilizing TAT-GLUT3(2D), we showed that blockage of activity-induced GLUT3 neuronal surface translocation leads to decreased glucose uptake and ATP production, impairing memory acquisition without affecting memory consolidation or retrieval in mice. Our results suggest that PKCε-mediated phosphorylation of GLUT3 is a key regulator of neuronal activity-induced GLUT3 plasma membrane insertion and memory acquisition, advancing our understanding of the energy supply needed for memory acquisition.