LAUSR

Neurosteroid dehydroepiandrosterone (DHEA) has been reported to exert a potent neuroprotective effect against glutamate‐induced excitotoxicity. However, the underlying mechanism remains to be elucidated. One of the possible mechanisms may be an involvement of astrocytic glutamate transporter subtype‐1 (GLT‐1) that can quickly clear spilled glutamate at the synapse to prevent excitotoxicity. To examine the effect of DHEA on GLT‐1 activity, we measured synaptically induced glial depolarization (SIGD) in the dentate gyrus (DG) of adult rats by applying an optical recording technique to the hippocampal slices stained with voltage‐sensitive dye RH155. Bath‐application of DHEA for 10 min dose‐dependently increased SIGD without changing presynaptic glutamate releases, which was sensitive to the GLT‐1 blocker DHK. Patch‐clamp recordings in astrocytes showed that an application of 50 μM DHEA increased glutamate‐evoked inward currents (Iglu) by approximately 1.5‐fold, which was dependent on the GLT‐1 activity. In addition, the level of biotinylated GLT‐1 protein in the surface of astrocytes was significantly elevated by DHEA. The DHEA‐increased SIGD, Iglu, and GLT‐1 translocation to the cell surface were blocked by the σ1R antagonist NE100 and mimicked by the σ1R agonist PRE084. DHEA elevated the phosphorylation level of PKC in a σ1R‐dependent manner. Furthermore, the PKC inhibitor chelerythrine could prevent the DHEA‐increased SIGD, Iglu, and GLT‐1 translocation. Collectively, present results suggest that DHEA enhances the activity and translocation to cell surface of astrocytic GLT‐1 mainly via σ1R‐mediated PKC cascade.