Prevention of normally occurring and deafferentation-induced neuronal death in chick brainstem auditory neurons by periodic blockade of AMPA/kainate receptors.

The role of glutamate receptors in regulating programmed neuronal death and deafferentation-induced neuronal death in the brainstem auditory nuclei was studied by in ovo drug administration to chick embryos. The nucleus laminaris (NL) undergoes programmed developmental cell death of 19% between embryonic day 9 (E9) and E17. The AMPA/kainate receptor antagonist CNQX, when administered at doses of 200-300 microg/d from E8 to E15, prevented programmed neuronal death in NL through at least posthatching day 8, without producing anatomical or behavioral abnormalities. 3-((RS)-2-Carboxypiperazin-4-yl)-propyl-1-phos-phonic acid, an antagonist of NMDA receptors, had no effect on normal cell death in the NL. CNQX, given from E8 to E15 or only from E8 to E10, also blocked the 33% neuronal loss in the nucleus magnocellularis (NM) that follows surgical destruction of the otocyst on E3, a procedure that deafferents NM neurons by preventing formation of the cochlear nerve. Treatment either with CNQX or the more highly selective NBQX from E8 to E10, before the onset of synaptic transmission in NM and NL, was also effective in preventing normal neuronal death in NL. Analysis of the effects of CNQX or NBQX on spontaneous embryonic motility at E10 showed that the doses effective in preventing neuronal death suppressed motility for <8 hr. We conclude that periodic blockade of AMPA/kainate receptors can protect CNS neurons against subsequent programmed cell death or deafferentation-induced death.