REGULATION AND FUNCTION OF THE GLUCOSE TRANSPORTER GLUT4 IN THE HIPPOCAMPUS

Glucose is the main energy source of the brain; however, how glucose is metabolized by different brain cells is still under debate. Neurons and astrocytes express different glucose transporters (GLUTs), but only neurons express the insulin-sensitive glucose transporter GLUT4, whose surface expression is under tight regulation in adipocytes and myocytes. To get a better understanding of brain metabolism, our group aims to characterize the regulation and function of GLUT4 in postsynaptic compartments of hippocampal neurons. Performing immunohistochemistry assays in organotypic hippocampal slice cultures, we first found that the surface to total ratio of recombinant GFP-tagged GLUT4 is higher in dendritic spines than in dendrites under basal conditions. Interestingly, we found that surface GFP-GLUT4 undergoes continuous recycling in a glucose- and sex-dependent manner. Then, to understand the functional role of GLUT4 in synaptic transmission and plasticity, we performed electrophysiological field recordings in acute hippocampal slices using the GLUT4-specific inhibitor indinavir. We found that acute application of indinavir decreases basal transmission at CA3-to-CA1 synapses, which seems to be driven by a decrease in the AMPA-receptor recycling. We are now studying the mechanisms underlying GLUT4-dependent basal transmission through rescue experiments, which will also show the metabolic pathway that glucose undergoes following GLUT4-mediated uptake. In parallel, we are performing proteomic analysis in acute hippocampal slices treated with indinavir to further elucidate the functional role of GLUT4. Overall, this research points to GLUT4 as a neuronal glucose provider needed for synaptic activity and may reveal differential regulation depending on the sex.