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The Journal of Neuroscience, April 1, 1998, 18(7):2437-2448

Dentate Gyrus Basket Cell GABA_A Receptors Are Blocked by Zn²⁺ via Changes of Their Desensitization Kinetics: An In Situ Patch-Clamp and Single-Cell PCR Study

Thomas Berger¹, Cordelia Schwarz², Udo Kraushaar¹, and Hannah Monyer²

¹ Institute of Physiology, University of Freiburg, D-79104 Freiburg, Germany, and ² Center of Molecular Biology (ZMBH), University of Heidelberg, D-69120 Heidelberg, Germany

Although GABA type A receptors (GABA_ARs) in principal cells have been studied in detail, there is only limited information about GABA_ARs in interneurons. We have used the patch-clamp technique in acute rat hippocampal slices in combination with single-cell PCR to determine kinetic, pharmacological, and structural properties of dentate gyrus basket cell GABA_ARs. Application of 1 mM GABA (100 msec) to nucleated patches via a piezo-driven fast application device resulted in a current with a fast rise and a marked biexponential decay (time constants 2.4 and 61.8 msec). This decay could be attributed to strong receptor desensitization. Dose-response curves for the peak and the slow component yielded EC₅₀ values of 139 and 24 µM, respectively. Zn²⁺ caused a marked blocking effect on both the peak and the slow component via a noncompetitive mechanism (IC₅₀ values of 8 and 16 µM). This led to an acceleration of the slow component as well as a prolongation of recovery from desensitization. Zn²⁺ sensitivity was suggested to depend on the absence of -subunits in GABA_ARs. To test this hypothesis we performed single-cell reverse transcription PCR that revealed primarily the presence of ₂-, ₂-, ₃-, ₁-, and ₂-subunit mRNAs. In addition, flunitrazepam increased the receptor affinity for its agonist, indicating the presence of functional benzodiazepine binding sites, i.e., -subunits. Thus, additional factors seem to co-determine the Zn²⁺ sensitivity of native GABA_ARs. The modulatory effects of Zn²⁺ on GABA_AR desensitization suggest direct influences on synaptic integration via changes in inhibition and shunting at GABAergic synapses.

Key words: rat; GABA receptor; kinetics; desensitization; deactivation; pharmacology; benzodiazepines; flunitrazepam; Zn²⁺; patch-clamp in situ; nucleated patch; fast application; single-cell PCR; subunits; mRNA

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1872437-12$05.00/0

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