Long-term exposure to high glucose induces changes in the expression of AMPA receptor subunits and glutamate transmission in primary cultured cortical neurons.

Hyperglycemia, which occurs under the diabetic conditions, induces serious diabetic complications. Diabetic encephalopathy has been defined as one of the major complications of diabetes, and is characterized by neurochemical and neurodegenerative changes. However, little is known about the effect of long-term exposure to high glucose on neuronal cells. In the present study, we showed that exposure to glutamate (100 mM) for 7 days induced toxicity in primary cortical neurons using the MTT assay. Additionally, high glucose increased the sensitivity of AMPA- or NMDA-induced neurotoxicity, and decreased extracellular glutamate levels in primary cortical neurons. In Western blot analyses, the protein levels of the GluA1 and GluA2 subunits of the AMPA receptor as well as synaptophysin in neurons treated with high glucose were significantly increased compared with the control (25 mM glucose). Therefore, long-term exposure to high glucose induced neuronal death through the disruption of glutamate homeostasis.

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 ß-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.