N-METHYL-D-ASPARTATE-MEDIATED GLUTAMATE TOXICITY IN THE DEVELOPING RABBIT RETINA

Extracellular levels of endogenous glutamate are relatively high in th e developing rabbit retina but nonetheless appear to promote cell surv ival and developmental processes at concentrations considered toxic in the adult, We wished to examine the development of retinal susceptibi lity to glutamate toxicity as well as the protective effects of two N- methyl-D-aspartate (NMDA) antagonists, 2-amino-5-phosphono-5-valeric a cid (APV) and dextromethorphan (Dex), and the nitric oxide synthase (N OS) inhibitor, N-G-methyl-L-arginine (metARG), One day in vitro retina l explants of adult and neonatal rabbits were incubated with various a gonists and antagonists, and stained with trypan blue to visualize nec rotic cells, The density of the necrotic cells was analyzed using the Zeiss Video-plan 2. Immature neurons were approximately 10-fold less s ensitive to NMDA toxicity compared to the adult, Although both NMDA an tagonists and metARG provided marked protection for adult retinal neur ons against glutamate toxicity, the modest susceptibility of the immat ure neuron was blocked only by Dex and not APV or metARG, At least two factors may contribute to the ability of the neonatal retina to survi ve in the presence of high levels of endogenous extracellular glutamat e, First, the 10-fold developmental increase in NMDA toxicity occurs s imultaneously with a 12-15-fold downregulation of extracellular glutam ate, probably through the actions of maturing Muller cells, Second, th e NMDA/NO excitotoxic pathway may not be active at birth since an NOS inhibitor had little effect at this stage and our previous morphologic al data demonstrate that NOS-containing cells are not present in their mature configuration until the second postnatal week. (C) 1997 Wiley- Liss, Inc.