Zinc selectively blocks neurosteroid-sensitive extrasynaptic δGABAA receptors in the hippocampus

Abstract

Zinc (Zn2+) is an essential cofactor in mammalian cells and neurons. Zn2+ is released from synaptic vesicles of certain nerve terminals in the hippocampus during neuronal activity. Zn2+ has been shown to inhibit synaptic GABAA receptors and alter the hippocampal network excitability. However, the ability of Zn2+ to block extrasynaptic receptors remains unclear. Endogenous neurosteroids, such as allopregnanolone (AP), regulate neuronal excitability by allosteric activation of synaptic and extrasynaptic GABAA receptors. Neurosteroids activate extrasynaptic δGABAA receptor-mediated tonic inhibition in dentate gyrus granule cells (DGGCs), thereby contributing to the regulation of downstream circuit excitability. Here we report a novel inhibitory role of Zn2+ at neurosteroid-sensitive, extrasynaptic δGABAA receptors by electrophysiological recordings in DGGCs from adult mice. Zn2+ displayed a concentration-dependent, reversible noncompetitive blockade of AP-sensitive tonic current in DGGCs (IC50, 16 μM). Tonic current was fully blocked by Zn2+, akin to the GABAA receptor antagonist gabazine. Zn2+ inhibition of tonic current was lacking in DGGCs from δ-subunit knock-out mice. Moreover, AP-activated synaptic receptor-mediated phasic currents were not affected by Zn2+. Finally, intrahippocampal infusion of Zn2+ elicited rapid epileptiform activity and significantly blocked the antiseizure activity of AP in the kindling model of epilepsy. Thus, Zn2+ inhibition of neurosteroid-sensitive, extrasynaptic GABAA receptors in the hippocampus has direct implications in many brain hyperexcitability conditions, such as seizures, epileptogenesis, and epilepsy. Zn2+ interactions may aid to further understand the physiology of extrasynaptic GABAA receptors.