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Volume 17, Number 22, Issue of November 15, 1997 pp. 8804-8816
Excitotoxicity in the Enteric Nervous System
Received July 16, 1997; revised Aug. 26, 1997; accepted Aug. 28, 1997.
Annette L. Kirchgessner, Min-Tsai Liu, and Frederick Alcantara Department of Anatomy and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York 10032
Glutamate, the major excitatory neurotransmitter in the CNS, is also an 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 stimulation of enteric ganglia by glutamate caused necrosis and apoptosis in enteric neurons. Acute and delayed cell deaths were observed. Glutamate neurotoxicity was mimicked by NMDA and blocked by the NMDA antagonist D-2-amino-5-phosphonopentanoate. Excitotoxicity was more pronounced in cultured enteric ganglia than in intact preparations of bowel, presumably because of a reduction in glutamate uptake. Glutamate-immunoreactive 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 varicosities ("blebs") on neurites. Blebs formed close to neurite intersections and were enriched in mitochondria, as revealed by rhodamine 123 staining. Kainic acid also produced a loss of mitochondrial membrane potential in cultured enteric neurons at sites where blebs tended to form. These observations demonstrate, for the first time, excitotoxicity in the ENS and suggest that overactivation of enteric glutamate receptors may contribute to the intestinal damage produced by anoxia, ischemia, and excitotoxins present in food.
Key words: necrosis; apoptosis; NMDA; kainic acid; glutamate transporters; bleb formation; rhodamine 123
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