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The Journal of Neuroscience, November 19, 2003, 23(33):10650-10661

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Cellular/Molecular
Perisynaptic Localization of Subunit-Containing GABA_A Receptors and Their Activation by GABA Spillover in the Mouse Dentate Gyrus

Weizheng Wei,^1,3 Nianhui Zhang,^2,3 Zechun Peng,^2,3 Carolyn R. Houser,^2,3,4 and Istvan Mody^1,3

Departments of ¹Neurology and Physiology and ²Neurobiology, and ³Brain Research Institute, The David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095, and ⁴Research Service, Department of Veterans Affairs Greater Los Angeles Healthcare System, West Los Angeles, Los Angeles, California 90073

In cerebellar granule cells, subunit-containing GABA_A receptors are found exclusively at extrasynaptic sites, but their subcellular distribution in other brain areas is poorly understood. We examined the anatomical localization and physiological activation of these receptors in adult mouse dentate gyrus granule cells. Immunocytochemistry revealed a high density of subunits in the molecular layer and a much lower density in the cell body layer. At the ultrastructural level, immunogold-labeled subunits were found at the edge of symmetric synapses on granule cell dendrites. Functional correlates of this perisynaptic localization were obtained by comparing inhibitory responses in subunit-deficient (-/-) and wild-type (wt) mice. In whole-cell recordings at 22°C, the weighted decay time constants (_w) of spontaneous IPSCs (sIPSCs) were significantly longer in wt mice but were similar at 34°C, reflecting the role of temperature-dependent GABA uptake in shaping sIPSC decay. IPSCs evoked by minimal stimulation (eIPSCs) near the somata had similar _w in -/- and wt mice, but eIPSCs elicited from dendritic sites decayed significantly more slowly in wt mice, consistent with a higher density of subunit-containing receptors in the molecular layer. The _w of dendritic eIPSCs of wt mice were shortened by ZnCl₂ (10 µM), reflecting the high Zn²⁺ sensitivity of subunit-containing GABA_A receptors, and were prolonged by the GAT-1 GABA transporter inhibitor NO711 (10 µM). Our results demonstrate a perisynaptic localization of subunit-containing GABA_A receptors and indicate that these receptors can be activated by GABA overspill in the molecular layer.

Key words: hippocampus; IPSCs; immunocytochemistry; GABA uptake; postembedding immunogold; zinc

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Received Aug 18, 2003; revised September 29, 2003; accepted October 2, 2003.

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