Differential effects of zinc on native GABA A receptor function in rat hippocampus and cerebellum

Abstract

Hippocampal noradrenergic and cerebellar glutamatergic granule cell axon terminals possess GABA A receptors mediating enhancement of noradrenaline and glutamate release, respectively. The hippocampal receptor is benzodiazepine-sensitive, whereas the cerebellar one is not affected by benzodiazepine agonists, indicating the presence of an α6 subunit. We tested here the effects of Zn 2+ on these two native GABA A receptor subtypes using superfused rat hippocampal and cerebellar synaptosomes. In the cerebellum, zinc ions strongly inhibited (IC 50≃1 μM) the potentiation of the K +-evoked [ 3H] d-aspartate release induced by GABA. In contrast, the GABA-evoked release of [ 3H]noradrenaline from hippocampal synaptosomes was much less sensitive to Zn 2+ (IC 50>30 μM). The effects of Zn 2+ were then studied in two rat lines selected for high (ANT) and low (AT) alcohol sensitivity because granule cell GABA A receptors in ANT, but not AT, rats respond to benzodiazepine agonists due to a critical mutation in the α6 subunit. GABA increased the K +-evoked release of [ 3H] dCNS regions-aspartate from cerebellar synaptosomes of AT and ANT rats, an effect prevented by the GABA A selective antagonist bicuculline. In AT rat cerebellum, the effect of GABA was strongly inhibited by Zn 2+ (IC 50≤1 μM), whereas in ANT rats, the divalent cation was about 100-fold less potent. Thus, native benzodiazepine-sensitive GABA A receptors appear largely insensitive to functional inhibition by Zn 2+ and vice versa. Changes in sensitivity to Zn 2+ inhibition consequent to mutations in cerebellar granule cell GABA A receptor subunits may lead to changes in glutamate release from parallel fibers onto Purkinje cells and may play important roles in cerebellar dysfunctions.