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The Journal of Neuroscience, December 15, 1999, 19(24):10803-10812

Opposing Effects of Excitatory Amino Acids on Chick Embryo Spinal Cord Motoneurons: Excitotoxic Degeneration or Prevention of Programmed Cell Death

Jerònia Lladó¹, Jordi Calderó¹, Joan Ribera¹, Olga Tarabal¹, Ronald W. Oppenheim², and Josep E. Esquerda¹

¹ Unitat de Neurobiologia Cel·lular, Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, E25198 Lleida, Catalonia, Spain, and ² Department of Neurobiology and Anatomy and Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Acute administration of a single dose of NMDA on embryonic day (E) 7 or later induces a marked excitotoxic injury in the chick spinal cord, including massive necrotic motoneuron (MN) death. When the same treatment was performed before E7, little, if any, excitotoxic response was observed. Chronic treatment with NMDA starting on E5 prevents the excitotoxic response produced by a later "acute" administration of NMDA. Additionally, chronic NMDA treatment also prevents the later excitotoxic injury induced by non-NMDA glutamate receptor agonists, such as kainate or AMPA. Chronic NMDA treatment also reduces normal MN death when treatment is maintained during the period of naturally occurring programmed cell death (PCD) of MNs and rescues MNs from PCD induced by early peripheral target deprivation. The trophic action of chronic NMDA treatment appears to involve a downregulation of glutamate receptors as shown by both a reduction in the obligatory NR1 subunit protein of the NMDA receptor and a decrease in the kainate-induced Co²⁺ uptake in MNs. Both tolerance to excitotoxicity and trophic effects of chronic NMDA treatment are prevented by the NMDA receptor antagonist MK-801. Additionally, administration of MK-801 alone results in an increase in MN PCD. These data indicate for the first time that early activation of NMDA receptors in developing avian MNs in vivo has a trophic, survival-promoting effect, inhibiting PCD by a target-independent mechanism that involves NMDA receptor downregulation.

Key words: excitatory amino acids; NMDA; motoneurons; programmed cell death; chick embryo; spinal cord; excitotoxicity; glutamate-induced neuroprotection

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Copyright © 1999 Society for Neuroscience  0270-6474/99/192410803-10$05.00/0

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