GABA A receptor sites in the developing human foetus

Abstract

GABA A receptor sites were characterised in cerebral cortex tissue samples from deceased neurologically normal infants who had come to autopsy during the third trimester of pregnancy. Pharmacological parameters were obtained from homogenate binding studies which utilised the ‘central-type’ benzodiazepine ligands [ 3H]diazepam and [ 3H]flunitrazepam, and from the GABA activation of [ 3H]diazepam binding. It was found that the two radioligands behaved differently during development. The affinity of [ 3H]flunitrazepam for its binding site did not vary significantly between preparations, whereas the [ 3H]diazepam K D showed marked regional and developmental variations: infant tissues showed a distinctly lower affinity than adults for this ligand. The density of [ 3H]flunitrazepam binding sites increased ∼35% during the third trimester to reach adult levels by term, whereas [ 3H]diazepam binding capacity declined slightly but steadily throughout development. The GABA activation of [ 3H]diazepam binding was less efficient early in the trimester, in that the affinity of the agonist was significantly lower, though it rose to adult levels by term. The strength of the enhancement response increased to adult levels over the same time-frame. The results strongly suggest that the subunit composition of cortical GABA A sites changes significantly during this important developmental stage.