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High-Affinity, Slowly Desensitizing GABA_A Receptors Mediate Tonic Inhibition in Hippocampal Dentate Granule Cells

Department of Neurology, University of Virginia-Health Sciences Center, Charlottesville, Virginia

The tonic form of GABA-mediated inhibition requires the presence of slowly desensitizing GABA_A receptors with high affinity, which has not yet been directly demonstrated in hippocampal neurons. Low concentration of GABA (1 µM) persistently increased baseline noise, increased membrane slope conductance, but did not affect spontaneous inhibitory postsynaptic currents (sIPSCs) in dentate granule cells (DGCs). Higher concentrations of GABA (10–100 µM) desensitized synaptic currents quickly, and there was a large residual current. Saturating concentration of GABA (1 mM) completely desensitized synaptic currents and revealed a slowly desensitizing, persistent current. Penicillin (300 µM) inhibited baseline noise without affecting mean current and inhibited decay time of sIPSCs. GABA_A receptors mediating baseline noise in DGCs were sensitive to allopregnanolone, furosemide, and loreclezole and insensitive to diazepam and zolpidem. These studies demonstrate persistently open GABA_A receptors on DGCs with high affinity for GABA, slow desensitization rate, and pharmacological properties similar to those of recombinant receptors containing ₄, ₁, and the subunits.

Address correspondence to: Dr. Zakaria Mtchedlishvili, Department of Neurology, Box 800394, University of Virginia-Health Sciences Center, Charlottesville, VA 22908. E-mail: zm5e{at}virginia.edu

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