title: Zinc Selectively Blocks Neurosteroid-Sensitive Extrasynaptic δGABAA Receptors in the Hippocampus.
abstract: Zinc (Zn(2+)) is an essential cofactor in mammalian cells and neurons. Zn(2+) is released from synaptic vesicles of certain nerve terminals in the hippocampus during neuronal activity. Zn(2+) has been shown to inhibit synaptic GABAA receptors and alter the hippocampal network excitability. However, the ability of Zn(2+) 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 Zn(2+) at neurosteroid-sensitive, extrasynaptic δGABAA receptors by electrophysiological recordings in DGGCs from adult mice. Zn(2+) displayed a concentration-dependent, reversible noncompetitive blockade of AP-sensitive tonic current in DGGCs (IC50, 16 μm). Tonic current was fully blocked by Zn(2+), akin to the GABAA receptor antagonist gabazine. Zn(2+) 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 Zn(2+) Finally, intrahippocampal infusion of Zn(2+) elicited rapid epileptiform activity and significantly blocked the antiseizure activity of AP in the kindling model of epilepsy. Thus, Zn(2+) inhibition of neurosteroid-sensitive, extrasynaptic GABAA receptors in the hippocampus has direct implications in many brain hyperexcitability conditions, such as seizures, epileptogenesis, and epilepsy. Zn(2+) interactions may aid to further understand the physiology of extrasynaptic GABAA receptors.
  
  
  
  Zn(2+) is most abundant in the synaptic vesicles of hippocampal mossy fibers. Zn(2+) release occurs with neuronal excitation, including seizure events, and exerts powerful excitability effects in the hippocampus circuits. Zn(2+) inhibits synaptic GABAA receptors, but its interaction is less well appreciated at the extrasynaptic receptors, which respond sensitively to endogenous neurosteroids. Here, we describe selective functional blockade by Zn(2+) of neurosteroid-sensitive, extrasynaptic GABAA receptors in the mouse hippocampus dentate gyrus, a key region associated with epilepsy and memory disorders. By demonstrating that extracellular Zn(2+) prevents neurosteroid augmentation of tonic current and protection against limbic seizures, our findings provide novel implications of this potential antagonistic interaction in a variety of neurological conditions.
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas 77807.
authors.forename: Chase Matthew
authors.initials: CM
authors.lastname: Carver
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas 77807.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Chuang
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas 77807 reddy@medicine.tamhsc.edu.
authors.forename: Doodipala Samba
authors.identifier: 0000-0003-2735-9550
authors.initials: DS
authors.lastname: Reddy
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000008:administration & dosage; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D015032:Zinc / Q000008:administration & dosage*
chemical_list: D018756:GABA Antagonists; D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A; D015032:Zinc
keywords: GABA receptor; epilepsy; extrasynaptic; neurosteroid; tonic inhibition; zinc