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

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Glucose transporter 3 (GLUT3) is essential for neuronal glucose uptake and rapidly moves to the plasma membrane during neural activity.
• The exact molecular mechanisms and physiological significance of GLUT3 translocation are not fully understood, limiting our knowledge of how glucose metabolism supports brain function.

Purpose of the Study:

• To elucidate the molecular mechanisms regulating GLUT3 translocation to the plasma membrane in response to neuronal activation.
• To investigate the functional role of activity-dependent GLUT3 translocation in cognitive processes, specifically memory acquisition.

Main Methods:

• Identified specific phosphorylation sites on GLUT3 (Thr232 and Ser246) targeted by PKCε upon neuronal activation.
• Developed a peptide inhibitor, TAT-GLUT3(2D), to block GLUT3-KLC1 binding and prevent activity-dependent GLUT3 translocation.
• Assessed the impact of blocked GLUT3 translocation on glucose uptake, ATP production, and memory functions in mice.

Main Results:

• PKCε phosphorylates GLUT3 at Thr232 and Ser246, enhancing its interaction with KLC1 and promoting plasma membrane insertion.
• Blocking GLUT3 translocation with TAT-GLUT3(2D) reduced neuronal glucose uptake and ATP levels.
• Impairment of activity-induced GLUT3 translocation led to deficits in memory acquisition, but not memory consolidation or retrieval, in mice.

Conclusions:

• PKCε-mediated phosphorylation of GLUT3 is a critical regulator of its plasma membrane insertion during neuronal activity.
• Activity-dependent GLUT3 translocation is essential for supporting the energy demands of memory acquisition.
• This study advances the understanding of glucose metabolism's role in memory formation.