ZINC AND GABAA RECEPTOR PLASTICITY

University Of California Los Angeles, Los Angeles CA

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Abstract

The present proposal is aimed at uncovering the functional outcome of gamma-aminobutyric acid type A (GABA/A) receptor plasticity in hippocampal inhibitory synapses. The proposed experiments will also elucidate the pathological consequence of the plastic conversion of zinc (Zn2+)- insensitive synaptic GABA/A receptors into Zn2+-sensitive ones, shared by two experimental models of temporal lobe epilepsy. The general hypothesis is that kindling and pilocarpine-induced epilepsy are associated with critical subunit-specific plastic changes of synaptic GABA/A receptors in hippocampal neurons leading to a change in inhibitory function. Specifically, in dentate gyrus granule cells, these alterations result in an enhanced blocking action of the endogenous GABA/A receptor modulatory ZN2+, which upon its release from sprouted mossy fiber terminals will severely impair GABAergic inhibition. First, collaborative studies with other members of the Program Project will establish how, after pilocarpine treatment, the loss of alpha5 subunits from CA2/CA1 pyramidal cells translates into changes in the properties of inhibitory synapses. Through single-channel and whole-cell patch-clamp recordings in the two epilepsy models we will then establish the characteristics of synaptic GABA/A receptors typified by an altered Zn2+-sensitivity. With other Program Project members, subunit-specific antibodies will be used to probe the subunit composition on the altered receptors, and by reconstituting cloned subunits in expression systems, we will attempt to mimic the properties of native GABA/A receptors before and after the pathological plasticity. Furthermore, we will investigate the relationship between GABA/A receptor plasticity and the endogenous Zn2+ found in sprouted mossy fiber terminals. As Zn2+ can be released from these terminals during heightened neuronal activity, abnormally elevated extracellular Zn2+ levels may be present during hippocampal seizures. Because Zn2+ is a negative allosteric modulatory of some GABA/A receptors, a chronically enhanced Zn2+ release could by itself lead to GABA/A receptor plasticity. This hypothesis will be addressed by perfusing Zn2+, its chelators, and by experimentally reducing the amount of mossy fiber sprouting responsible for the excess Zn2+ delivery. Since Zn2+ may affect a variety of channels, other possible pre- and post-synaptic factors involved in the Zn2+-dependent regulation of GABA synapses will be explored. The proposed studies are expected to reveal critical aspects of long-term regulation of GABA synapses, leading to a better understanding of the pathological consequences of GABA/A receptor plasticity. Our findings could provide the basis for novel and rational therapeutical approaches against devastating psychiatric and neurodegenerative disorders including anxiety, stress, stroke, and epilepsy.