EXCITOTOXICITY IN THE ENTERIC NERVOUS-SYSTEM

Glutamate, the major excitatory neurotransmitter in the CNS, is also a n excitatory neurotransmitter in the enteric nervous system (ENS). We tested the hypothesis that excessive exposure to glutamate, or related agonists, produces neurotoxicity in enteric neurons. Prolonged stimul ation of enteric ganglia by glutamate caused necrosis and apoptosis in enteric neurons. Acute and delayed cell deaths were observed. Glutama te neurotoxicity was mimicked by NMDA and blocked by the NMDA antagoni st D-2-amino-5-phosphonopentanoate. Excitotoxicity was more pronounced in cultured enteric ganglia than in intact preparations of bowel, pre sumably because of a reduction in glutamate uptake. Glutamate-immunore active neurons were found in cultured myenteric ganglia, and a subset of enteric neurons expressed NMDA (NR1, NR2A/B), AMPA (GluR1, GluR2/3) , and kainate (GluR5/6/7) receptor subunits. Glutamate receptors were clustered on enteric neurites. Stimulation of cultured enteric neurons by kainic acid led to the swelling of somas and the growth of varicos ities (''blebs'') on neurites. Blebs formed close to neurite intersect ions and were enriched in mitochondria, as revealed by rhodamine 123 s taining. Kainic acid also produced a loss of mitochondrial membrane po tential in cultured enteric neurons at sites where blebs tended to for m. These observations demonstrate, for the first time, excitotoxicity in the ENS and suggest that overactivation of enteric glutamate recept ors may contribute to the intestinal damage produced by anoxia, ischem ia, and excitotoxins present in food.