Opposing effects of excitatory amino acids on chick embryo spinal cord motoneurons: Excitotoxic degeneration or prevention of programmed cell death

Acute administration of a single dose of NMDA on embryonic day (E) 7 or lat er induces a marked excitotoxic injury in the chick spinal cord, including massive necrotic motoneuron (MN) death. When the same treatment was perform ed before E7, little, if any, excitotoxic response was observed. Chronic tr eatment with NMDA starting on E5 prevents the excitotoxic response produced by a later "acute" administration of NMDA. Additionally, chronic NMDA trea tment also prevents the later excitotoxic injury induced by non-NMDA glutam ate 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 rec eptors as shown by both a reduction in the obligatory NR1 subunit protein o f the NMDA receptor and a decrease in the kainate-induced Co2+ uptake in MN s. Both tolerance to excitotoxicity and trophic effects of chronic NMDA tre atment 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 dev eloping avian MNs in vivo has a trophic, survival-promoting effect, inhibit ing PCD by a target-independent mechanism that involves NMDA receptor downr egulation.