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1 Department of Clinical and Experimental Epilepsy, Institute of Neurology, UCL, London, United Kingdom
2 Department of Psychology, Neuroscience Institute, Dalhousie University, Halifax, Nova Scotia, Canada
* To whom correspondence should be addressed. E-mail: d.kullmann{at}ion.ucl.ac.uk.
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 (TPEN) had no effect on stratum- radiatum-evoked 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 stratum radiatum (to recruit local interneurons), or in the stratum 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.
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