2-Deoxy-D-Glucose Enhances Tonic Inhibition Through the Neurosteroid-Mediated Activation of Extrasynaptic GABA-A Receptors

The study demonstrated that 2-deoxy-d-glucose (2-DG), a glucose analog that inhibits glycolytic enzymes, enhanced tonic inhibition in the brain through the activation of extrasynaptic GABAA receptors mediated by neurosteroids. This effect was observed in hippocampal slices and involved the activation of ATP-sensitive potassium (KATP) channels and bicuculline-sensitive tonic currents. The enhancement of GABAergic tonic currents by 2-DG was blocked by inhibitors of the neurosteroidogenesis pathway, indicating the role of neurosteroids in this process. Additionally, the study found that 2-DG's enhancement of KATP currents regulated the intrinsic firing rate of granule cells, while the increase in GABAergic tonic currents reduced the frequency of interictal events induced by a convulsive agent. This research highlighted the potential of 2-DG as an antiseizure agent through its modulation of tonic GABAergic inhibition.