GABA transient sets the susceptibility of mIPSCs to modulation by benzodiazepine receptor agonists in rat hippocampal neurons.
Benzodiazepines (BDZs) are known to increase the amplitude and duration of IPSCs. Moreover, at low [GABA], BDZs strongly enhance GABAergic currents suggesting the up-regulation of agonist binding while their action on gating remains a matter of debate. In the present study we have examined the impact of flurazepam and zolpidem on mIPSCs by investigating their effects on GABA(A)R binding and gating and by considering dynamic conditions of synaptic receptor activation. Flurazepam and zolpidem enhanced the amplitude and prolonged decay of mIPSCs. Both compounds strongly enhanced responses to low [GABA] but, surprisingly, decreased the currents evoked by saturating or half-saturating [GABA]. Analysis of current responses to ultrafast GABA applications indicated that these compounds enhanced binding and desensitization of GABA(A) receptors. Flurazepam and zolpidem markedly prolonged deactivation of responses to low [GABA] but had almost no effect on deactivation at saturating or half-saturating [GABA]. Moreover, at low [GABA], flurazepam enhanced desensitization-deactivation coupling but zolpidem did not. Recordings of responses to half-saturating [GABA] applications revealed that appropriate timing of agonist exposure was sufficient to reproduce either a decrease or enhancement of currents by flurazepam or zolpidem. Recordings of currents mediated by recombinant ('synaptic') alpha1beta2gamma2 receptors reproduced all major findings observed for neuronal GABA(A)Rs. We conclude that an extremely brief agonist transient renders IPSCs particularly sensitive to the up-regulation of agonist binding by BDZs.
Mozrzymas
Jerzy W
JW
Laboratory of Neuroscience, Department of Biophysics, Wrocław Medical University, Chałubiñskiego 3, 50-368 Wroclaw, Poland.
Wójtowicz
Tomasz
T
Piast
Michal
M
Lebida
Katarzyna
K
Wyrembek
Paulina
P
Mercik
Katarzyna
K
D000818:Animals; D002478:Cells, Cultured; D004594:Electrophysiology; D005479:Flurazepam / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D011725:Pyridines; D017981:Receptors, Neurotransmitter; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem; D005479:Flurazepam