Exendin (5-39), an antagonist of GLP-1 receptor, modulates synaptic transmission via glutamate uptake in the dentate gyrus

Extracellular concentrations of glutamate are mainly controlled by an astrocytic glutamate transporter, GLT-1. We previously reported that exendin (5-39) (Ex), an antagonist of the GLP-1 receptor, improved memory impairment in β-amyloid protein-treated rats. In this study, we investigated effects of Ex on synaptic transmission through astrocytic GLT-1 in the hippocampus. Continuous intracerebroventricular (i.c.v.) administration of Ex for 1-week increased GLT-1 protein levels in the hippocampus of 4-week-old male Wistar rats. For electrophysiological studies, hippocampal slices were prepared from these Ex-treated rats or vehicle-treated rats. Ex decreased fEPSP decay time, and increased the input–output relation and decreased the paired-pulse ratio in the dentate gyrus (DG). Furthermore, Ex inhibited long-term depression but not long-term potentiation in the DG. These effects were prevented by DHK, a specific GLT-1 inhibitor. In addition, glutamate uptake was significantly increased by Ex-treatment in cultured astrocytes. These results suggest that Ex modulates synaptic transmission and plasticity through astrocytic glutamate uptake in the DG.

► Exendin (5-39) (Ex) decreased fEPSP decay time in dentate gyrus (DG).
► Ex increased input–output relation and decreased paired-pulse ratio in DG.
► Ex inhibited the long-term depression in the DG, which were inhibited by a GLT-1 inhibitor.
► Ex increased GLT-1 protein in DG, and enhanced the glutamate up-take in cultured astrocyte.
► Ex modulates synaptic transmission and plasticity through GLT-1 in the DG.