Zinc reduces antiseizure activity of neurosteroids by selective blockade of extrasynaptic GABA-A receptor-mediated tonic inhibition in the hippocampus. Academic Article uri icon


  • Zinc is an abundant trace metal in the hippocampus nerve terminals. Previous studies demonstrate the ability of zinc to selectively block neurosteroid-sensitive, extrasynaptic GABA-A receptors in the hippocampus (Carver et al, 2016). Here we report that zinc prevents the seizure protective effects of the synthetic neurosteroid ganaxolone (GX) in an experimental model of epilepsy. GABA-gated and tonic currents were recorded from dissociated dentate gyrus granule cells (DGGCs), CA1 pyramidal cells (CA1PCs), and hippocampal slices from adult mice. Antiseizure effects of GX and the reversal of these effects by zinc were evaluated in fully-kindled mice expressing generalized (stage 5) seizures. In electrophysiological studies, zinc blocked the GABA-evoked and GX-potentiated GABA-gated chloride currents in DGGCs and CA1PCs in a concentration-dependent fashion similar to the competitive GABA-A receptor antagonists bicuculline and gabazine. Zinc completely blocked GX potentiation of extrasynaptic tonic currents, but not synaptic phasic currents. In hippocampus kindling studies, systemic administration of GX produced a dose-dependent suppression of behavioral and electrographic seizures in fully-kindled mice with complete seizure protection at the 10mg/kg dose. However, the antiseizure effects of GX were significantly prevented by intrahippocampal administration of zinc (ED50, 150M). The zinc antagonistic response was reversible as animals responded normally to GX administration 24h post-zinc blockade. These results demonstrate that zinc reduces the antiseizure effects of GX by selectively blocking extrasynaptic GABA-A receptors in the hippocampus. These pharmacodynamic interactions have clinical implications in neurosteroid therapy for brain conditions associated with zinc fluctuations.

published proceedings

  • Neuropharmacology

author list (cited authors)

  • Chuang, S., & Reddy, D. S.

citation count

  • 8

complete list of authors

  • Chuang, Shu-Hui||Reddy, Doodipala Samba

publication date

  • January 2019