Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons

Emma J. Prokic, Cathryn Weston, Naoki Yamawaki, Stephen D. Hall, Roland S.G. Jones, Ian M. Stanford, Graham Ladds*, Gavin L. Woodhall

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)192–205
Number of pages14
Early online date20 Mar 2015
Publication statusPublished - Aug 2015

Bibliographical note

© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (

Funding: Warwick Impact Fund, Warwick Research Development Fund (RD13301); Birmingham Science City Research Alliance; and BBSRC (BB/G01227X/1).


  • GABAA receptors
  • beta oscillations
  • tonic current
  • zolpidem
  • fast spiking interneurons
  • motor cortex


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