Modulation of glutamate transmission during amyotrophic lateral sclerosis : regulation of glutamate transporters and implication of neuroinflammation

Modifications in glutamate homeostasis together with gliosis and release of inflammatory mediators are hallmarks of amyotrophic lateral sclerosis (ALS). Some evidence suggests that neuroinflammatory mediators may have an influence on the regulation of glutamatergic targets including glutamate transporters. In the present thesis, we therefore aimed at investigating the regulation of glutamate transporters and the implication of neuroinflammation in the modulation of glutamatergic transmission during ALS. We characterized the regulation of glutamate transporters at different stages of ALS in the cortex and the lumbar spinal cord in a transgenic rat model expressing an ALS-associated human mutated form of the superoxide dismutase 1 (hSOD1G93A). We also examined the influence of pro-inflammatory cytokines on glutamatergic targets in astrocyte cultures from wild-type or hSOD1G93A rats. Results of the present thesis highlight different regulation profiles of GLT-1a and GLT-1b isoforms during ALS. In addition, we evidenced in wild-type astrocytes a difference of stability and regulation of the homo- and multimeric assemblies of GLT-1a and GLT-1b, likely due to interactions with scaffold proteins putatively stabilizing GLT-1b multimeric assemblies. Results also shed light on an important role of neuroinflammation on regulations of glutamatergic targets and a differential regulation between the splice variants GLT-1a and GLT-1b which could be of importance in the glutamate mediated excitotoxicity observed during ALS.