Prevention of Normally Occurring and Deafferentation-Induced Neuronal Death in Chick Brainstem Auditory Neurons by Periodic Blockade of AMPA/Kainate Receptors

Abstract

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 g/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)Ϫ2-Carboxypiperazin-4-yl)-propyl-1-phosphonic 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 Ͻ8 hr. We conclude that periodic blockade of AMPA/kainate receptors can protect CNS neurons against subsequent programmed cell death or deafferentation-induced death. Key words: neuroprotection; glutamate; programmed cell death; apoptosis; auditory system; cochlear nuclei; CNQX; NBQX; CPP; nucleus laminaris; nucleus magnocellularisModulation of glutamate receptor function can have profound effects on developing neurons. These effects, which are thought to depend on receptor-mediated changes in cytosolic calcium concentration, include changes in neurite outgrowth, synapse formation, expression of neurotrophins and their receptors, expression of the glutamate receptor, and neuronal survival (Mattson, 1996). Because the NMDA subtype of the glutamate receptor is prominent in many CNS regions during key periods in development and is a major source of calcium influx in many neurons (Mori and Mishina, 1995), the role of this receptor subtype in nervous system development has received extensive study (Scheetz and Constantine-Paton, 1994). The non-NMDA receptors, however, are the main mediators of excitatory neurotransmission (Collingridge and Lester, 1989;Bettler and Mulle, 1995) and in a number of CNS regions are also permeable to calcium ions (Jonas and Burnashev, 1995). Calcium-permeable AMPA /kainate receptors have been shown to confer susceptibility to excitotoxic death in cultured spinal cord neurons (Carriedo et al., 1996), and normal neuronal death in the chick spinal cord is increased by treatments purported to raise intracellular calcium levels (Ciutat et al., 1994). It is not known, however, whether non-NMDA receptors are important in controlling cell number during development.The present study examined th...

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“…3). This increase in relative cell number was not solely an adaptation to the wider frequency range of the auditory system because in owls the number of neurons per octave is larger than, for example, that of chickens [calculated from Winter and Schwartzkopf, 1961;Winter, 1963;Rubel et al, 1976;Parks, 1979;Fay, 1988;Solum et al, 1997].…”

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