EFFECTS OF EXCITATORY AMINO-ACIDS ON NEUROMUSCULAR DEVELOPMENT IN THECHICK-EMBRYO

To investigate the presumptive role of excitatory amino acids (EAAs) i n the regulation of normally occurring motoneuron (MN) death, chick em bryos were treated with the glutamate receptor antagonists dizocilpine maleate and -nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide disodi um. Both failed to alter the number of surviving MNs at the end of the critical period of programmed cell death. However, treatment with 3-( 2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, a competitive N-met hyl-D-aspartic acid (NMDA) receptor antagonist, was able to rescue a s ignificant number of MNs from death. Treatment with several EAA agonis ts induced extensive excitotoxic lesions in the spinal cord. MN degene ration induced by excitotoxins exhibited changes characteristic of nec rosis rather than apoptosis. However, when either 0.5 or 1 mg of NMDA was applied acutely on embryonic day (E) 7, about 50% of treated embry os failed to exhibit NMDA-induced excitoxicity but rather showed a cle ar reduction in the number of pyknotic MNs. This apparent neuroprotect ive effect of NMDA was also observed in a subset of embryos chronicall y treated with NMDA, in which an excessive number of MNs was detected when examined on E9. Surprisingly, in the same experiment other embryo s showed either normal or highly reduced MN numbers. Embryos with moto neuronal depletion induced by NMDA also showed a delayed impairment of later neuromuscular development with the appearance of degenerative c hanges in surviving MNs and apoptosis of skeletal muscle cells. Becaus e some of the alterations reported here are similar to those described in MN diseases, our experimental model may be useful for gaining insi ghts into the mechanisms that control both developmentally regulated a nd pathological MN death. (C) 1997 Wiley-Liss, Inc.