Differential and irreversible CNS ontogenic reduction in maximal MK-801 binding site number in the NMDA receptor after acute hypoxic hypoxia

Abstract

CNS exposure to hypoxia impairs excitatory and inhibitory neurotransmission. Our aim was to determine variations induced by normobaric acute hypoxic hypoxia (8% O 2 for 60 min) on the NMDA receptor complex, as well as their potential reversibility after normoxic recovery. To this end, [ 3H]MK-801 binding assays to a synaptic membrane fraction isolated from chick optic lobes were performed. Previous studies throughout development had disclosed a characteristic age-dependent pattern. Results at embryonic day (ED) 12 and 18 indicated two distinct MK-801 binding sites. Hypoxic treatment failed to alter either the high affinity site dissociation constant ( K d) or its maximal binding capacity ( B max), whereas the low affinity site B max was significantly decreased (50% and 30% at ED12 and 18, respectively), without alteration in its K d values. Hypoxic embryos restored for 48 h at ED12 to normoxic conditions displayed unchanged MK-801 binding reduction, unlike those treated likewise at ED18 whose values fully recovered control levels. To conclude, hypoxic treatment reduces low affinity MK-801 B max in the NMDA receptor which proves irreversible up to ED12. Such early neuronal vulnerability may be due to post-transcriptional changes, to endocytosis followed by receptor degradation, or alternatively to cell death.