Self-induced accumulation of glutamate in striatal astrocytes and basal ganglia excitotoxicity.

Abstract

Excitotoxicity induced by high levels of extracellular glutamate (GLU) has been proposed as a cause of cell degeneration in basal ganglia disorders. This phenomenon is normally prevented by the astrocytic GLU-uptake and the GLU-catabolization to less dangerous molecules. However, high-GLU can induce reactive gliosis which could change the neuroprotective role of astrocytes. The striatal astrocyte response to high GLU was studied here in an in vivo rat preparation. The transient striatal perfusion of GLU (1 h) by reverse microdialysis induced complex reactive gliosis which persisted for weeks and which was different for radial-like glia, protoplasmic astrocytes and fibrous astrocytes. This gliosis was accompanied by a persistent cytosolic accumulation of GLU (immunofluorescence quantif ied by confocal microscope), which persisted for weeks (self-induced glutamate accumulation), and which was associated to a selective decrease of glutamine synthetase activity. This massive and persistent self-induced glutamate accumulation in striatal astrocytes could be an additional factor for the GLU-induced excitotoxicity, which has been implicated in the progression of different basal ganglia disorders.