Hypoxia differentially reduces GABA(A) receptor density during embryonic chick optic lobe development

Abstract

It has been demonstrated that the CNS is severely affected by hypoxic-ischemic insults during the prenatal-perinatal period, including imbalance in excitatory and inhibitory neurotransmitter release. Using a previously developed model of acute normobaric hypoxic hypoxia on chick embryos, we studied alterations observed both on [3H]GABA binding saturation parameters and on lactate concentration on successive embryonic days (ED). While maximal density of GABA binding sites (Bmax) from the low-affinity site was significantly reduced in an age-dependent manner, earlier stages of development (ED12 and 16) proving more vulnerable (ED12: control = 5.48 +/- 0.20, hypoxia = 3.90 +/- 0.39 pmol/mg prot, P < .05; ED16: control = 3.89 +/- 0.26, hypoxia = 2.80 +/- 0.28 pmol/mg prot, P < .05), ligand affinity (Kd) values and kinetic constants of the high-affinity site remained unaltered. Not unlikely, a physiological hypoxic state prevailing from ED17 up to hatching time rendered the whole embryo less sensitive to an externally induced hypoxic state (ED17: control = 2.93 +/- 0.06, hypoxia = 2.38 +/- 0.04 pmol/mg prot, P < .05; ED18: control = 2.97 +/- 0.12, hypoxia = 2.87 +/- 0.27 pmol/mg prot). Lactate levels in chick optic lobe homogenates were constant during development. The increase observed after hypoxic treatment compared to control value was significant at all stages studied, but increased percentage changes proved similar, indicating that all days of development equally perceive externally induced hypoxia. In conclusion, the present work demonstrates that after normobaric hypoxic hypoxia at different embryonic days, the embryo senses the externally induced hypoxic state as from ED12, but the GABA(A) receptor is differentially affected. It may be speculated that a different subunit composition of GABA(A) receptor is assembled in order to build a more stable receptor capable of resisting the physiological hypoxic state observed during the last few days before hatching.