The dynamics of changes in hippocampal GABAergic system in rats exposed to early-life hypoxia-induced seizures

Abstract

Hypoxia-evoked seizures (H/S) early in life lead to multiple chronic neurological deficits. Here, we present the results of studying GABA release and uptake in hippocampal axon terminals of rats exposed to H/S at 10–12 days of age. We characterized (i) exocytotic release of GABA; (ii) the initial rate of GABA uptake; (iii) the regulation of GABA release by presynaptic GABAB receptors. Rats were used for experiments 2, 4 and 8 weeks after H/S. We found that exocytotic [3H]GABA release was higher in rats exposed to H/S, and a maximal difference in the release was observed between the control and experimental rats tested 2 weeks after H/S. In contrast, the initial rate of GABA uptake decreased with age, and this tendency was more pronounced in rats exposed to H/S. Using (±)-baclofen and SKF 97541 as agonists of GABAB receptor, we revealed that a significant difference in the auto-inhibition of exocytotic [3H]GABA release was detected only between the control and experimental adult rats (8 weeks after hypoxia). The inhibitory effect dropped dramatically in the control adults, but only slightly decreased in adult rats exposed to H/S, thus becoming threefold more potent after hypoxic injury. Together, the results show that H/S affects the dynamics of age-dependent changes in the GABAergic system, and that the enhanced GABAB receptor-mediated auto-inhibition can be an important factor in weakening the postsynaptic inhibition and in the development of hyperexcitability in rats exposed to H/S.