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GABA transient sets the susceptibility of mIPSCs to modulation by benzodiazepine receptor agonists in rat hippocampal neurons
Author(s) -
Mozrzymas Jerzy W.,
Wójtowicz Tomasz,
Piast Michał,
Lebida Katarzyna,
Wyrembek Paulina,
Mercik Katarzyna
Publication year - 2007
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2007.143602
Subject(s) - flurazepam , zolpidem , agonist , chemistry , gabaa receptor , gabaergic , neuroscience , pharmacology , gating , biophysics , receptor , benzodiazepine , biochemistry , biology , insomnia
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’) α1β2γ2 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.