Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons
| Autor: | Emma J, Prokic, Cathryn, Weston, Naoki, Yamawaki, Stephen D, Hall, Roland S G, Jones, Ian M, Stanford, Graham, Ladds, Gavin L, Woodhall |
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| Rok vydání: | 2014 |
| Předmět: |
Flumazenil
Male Patch-Clamp Techniques Dose-Response Relationship Drug Pyridines Pyramidal Cells Models Neurological Action Potentials Receptors GABA-A Tissue Culture Techniques Zolpidem Kinetics Inhibitory Postsynaptic Potentials Interneurons Animals GABA-A Receptor Agonists Rats Wistar Beta Rhythm GABA Modulators gamma-Aminobutyric Acid |
| Zdroj: | Neuropharmacology. 95 |
| ISSN: | 1873-7064 |
| Popis: | Tonic conductance mediated by extrasynaptic GABAA receptors has been implicated in the modulation of network oscillatory activity. Using an in vitro brain slice to produce oscillatory activity and a kinetic model of GABAA receptor dynamics, we show that changes in tonic inhibitory input to fast spiking interneurons underlie benzodiazepine-site mediated modulation of neuronal network synchrony in rat primary motor cortex. We found that low concentrations (10 nM) of the benzodiazepine site agonist, zolpidem, reduced the power of pharmacologically-induced beta-frequency (15-30 Hz) oscillatory activity. By contrast, higher doses augmented beta power. Application of the antagonist, flumazenil, also increased beta power suggesting endogenous modulation of the benzodiazepine binding site. Voltage-clamp experiments revealed that pharmacologically-induced rhythmic inhibitory postsynaptic currents were reduced by 10 nM zolpidem, suggesting an action on inhibitory interneurons. Further voltage-clamp studies of fast spiking cells showed that 10 nM zolpidem augmented a tonic inhibitory GABAA receptor mediated current in fast spiking cells whilst higher concentrations of zolpidem reduced the tonic current. A kinetic model of zolpidem-sensitive GABAA receptors suggested that incubation with 10 nM zolpidem resulted in a high proportion of GABAA receptors locked in a kinetically slow desensitized state whilst 30 nM zolpidem favoured rapid transition into and out of desensitized states. This was confirmed experimentally using a challenge with saturating concentrations of GABA. Selective modulation of an interneuron-specific tonic current may underlie the reversal of cognitive and motor deficits afforded by low-dose zolpidem in neuropathological states. |
| Databáze: | OpenAIRE |
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