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

Abstract

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.

Publication DOI: https://doi.org/10.1016/j.neuropharm.2015.03.006
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences > Clinical and Systems Neuroscience
College of Health & Life Sciences > Aston Institute of Health & Neurodevelopment (AIHN)
College of Health & Life Sciences
Additional Information: © 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Funding: Warwick Impact Fund, Warwick Research Development Fund (RD13301); Birmingham Science City Research Alliance; and BBSRC (BB/G01227X/1).
Uncontrolled Keywords: GABAA receptors,beta oscillations,tonic current,zolpidem,fast spiking interneurons,motor cortex,Neuroscience(all),Pharmacology, Toxicology and Pharmaceutics(all)
Publication ISSN: 1873-7064
Last Modified: 17 Jun 2024 07:15
Date Deposited: 02 Apr 2015 10:30
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2015-08
Published Online Date: 2015-03-20
Authors: Prokic, Emma J.
Weston, Cathryn
Yamawaki, Naoki
Hall, Stephen D.
Jones, Roland S.G.
Stanford, Ian M. (ORCID Profile 0000-0002-5677-8538)
Ladds, Graham
Woodhall, Gavin L. (ORCID Profile 0000-0003-1281-9008)

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