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J Neurophysiol 91: 1091-1096, 2004. First published October 15, 2003; doi:10.1152/jn.00755.2003
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Report

Endogenous Zinc Inhibits GABAA Receptors in a Hippocampal Pathway

Arnaud Ruiz1, Matthew C. Walker1, Ruth Fabian-Fine2 and Dimitri M. Kullmann1

1Institute of Neurology, University College London, London WC1N 3BG, United Kingdom; and 2Department of Psychology, Neuroscience Institute, Dalhousie University, Halifax, Nova Scotia B3H 4J1, Canada

Submitted 5 August 2003; accepted in final form 10 October 2003

Depending on their subunit composition, GABAA receptors can be highly sensitive to Zn2+. Although a pathological role for Zn2+-mediated inhibition of GABAA receptors has been postulated, no direct evidence exists that endogenous Zn2+ can modulate GABAergic signaling in the brain. A possible explanation is that Zn2+ 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 Zn2+. Here, we show, using combined Timm's method and post-embedding immunogold, that the same mossy fiber varicosities can contain both GABA and Zn2+. Chelating Zn2+ 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 Zn2+. 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 Zn2+ and are consistent with GABA release at Zn2+-containing mossy fiber synapses.

Address reprint requests and other correspondence to D. M. Kulmnann, (E-mail: d.kullmann{at}ion.ucl.ac.uk).




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