High-affinity, slowly desensitizing GABAA receptors mediate tonic inhibition in hippocampal dentate granule cells.
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 microM) 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 microM) 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 microM) 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 alpha(4), beta(1), and the delta subunits.
Mtchedlishvili
Zakaria
Z
Department of Neurology, University of Virginia-Health Sciences Center, Charlottesville, 22908, USA. zm5e@virginia.edu
Kapur
Jaideep
J
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D018891:Dentate Gyrus / Q000187:drug effects / Q000502:physiology*; D003975:Diazepam / Q000494:pharmacology; D004232:Diuretics / Q000494:pharmacology; D005665:Furosemide / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D010406:Penicillins / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000494:pharmacology; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000927:Anticonvulsants; D004232:Diuretics; D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D010406:Penicillins; D011725:Pyridines; D014230:Triazoles; D005680:gamma-Aminobutyric Acid; C066440:loreclezole; D000077334:Zolpidem; D005665:Furosemide; D003975:Diazepam