title: Endogenous zinc inhibits GABA(A) receptors in a hippocampal pathway.
abstract: Depending on their subunit composition, GABA(A) receptors can be highly sensitive to Zn(2+). Although a pathological role for Zn(2+)-mediated inhibition of GABA(A) receptors has been postulated, no direct evidence exists that endogenous Zn(2+) can modulate GABAergic signaling in the brain. A possible explanation is that Zn(2+) is mainly localized to a subset of glutamatergic synapses. Hippocampal mossy fibers are unusual in that they are glutamatergic but have also been reported to contain GABA and Zn(2+). Here, we show, using combined Timm's method and post-embedding immunogold, that the same mossy fiber varicosities can contain both GABA and Zn(2+). Chelating Zn(2+) with either calcium-saturated EDTA or N,N,N',N'-tetrakis (2-pyridylmethyl)ethylenediamine had no effect on stratum-radiatum-evoked inhibitory postsynaptic currents (IPSCs), but enhanced IPSCs evoked by stimuli designed to recruit dentate granule cells. We also show that IPSCs recorded in CA3 pyramidal neurons in acute hippocampal slices are depressed by exogenous Zn(2+). This depression was of similar amplitude whether the IPSCs were evoked by stimulation in s. radiatum (to recruit local interneurons) or in the s. granulosum of the dentate gyrus (to recruit mossy fibers). These results show for the first time that GABAergic IPSCs can be modulated by endogenous Zn(2+) and are consistent with GABA release at Zn(2+)-containing mossy fiber synapses.
authors.affiliation: Institute of Neurology, University College London, London WC1N 3BG, United Kingdom.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ruiz
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walker
authors.forename: Ruth
authors.initials: R
authors.lastname: Fabian-Fine
authors.forename: Dimitri M
authors.initials: DM
authors.lastname: Kullmann
mesh_terms: D000818:Animals; D002712:Chlorides / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D006168:Guinea Pigs; D006624:Hippocampus / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009434:Neural Pathways / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015032:Zinc / Q000502:physiology*; D017967:Zinc Compounds / Q000494:pharmacology
chemical_list: D002712:Chlorides; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D017967:Zinc Compounds; C016837:zinc chloride; D015032:Zinc