The Metabolic Disturbances of Motoneurons Exposed to Glutamate

Blandine Madji Hounoum, Hélène Blasco, Emmanuelle Coque, Patrick Vourc’h, Patrick Emond, Philippe Corcia, Christian R. Andres, Cédric Raoul, Sylvie Mavel

Glutamate-induced excitotoxicity is considered as one of the major pathophysiological factors of motoneuron death in amyotrophic lateral sclerosis and other motoneuron diseases. In order to expand our knowledge on mechanisms of glutamate-induced excitotoxicity, the present study proposes to determine the metabolic consequences of glutamate and astrocytes in primary enriched motoneuron culture. Using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS), we showed that the presence of astrocytes and glutamate profoundly modified the metabolic profile of motoneurons. Our study highlights for the first time that crosstalk between astrocytes and enriched motoneuron culture induced alterations in phenylalanine, tryptophan, purine, arginine, proline, aspartate, and glutamate metabolism in motoneurons. We observed that astrocytes modulate the sensitivity of motoneurons to glutamate, since metabolites altered by glutamate in motoneurons cultured alone were different (except 5-hydroxylysine) from those altered in co-cultured motoneurons. Our findings provide new insight into the metabolic alterations associated to astrocytes and glutamate in motoneurons and provide opportunities to identify novel therapeutic targets.