Prokic, Emma J., Weston, Cathryn, Yamawaki, Naoki , Hall, Stephen D., Jones, Roland S. G., Stanford, Ian M., Ladds, Graham and Woodhall, Gavin L. (2015) Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons. Neuropharmacology, 95 . pp. 192-205. doi:10.1016/j.neuropharm.2015.03.006

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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.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology
Divisions:	Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Interneurons, Motor cortex
Journal or Publication Title:	Neuropharmacology
Publisher:	Elsevier
ISSN:	0028-3908
Official Date:	August 2015
Dates:	Date Event August 2015 Published 20 March 2015 Available 8 March 2015 Accepted 9 February 2014 Updated 25 November 2014 Submitted
Volume:	95
Number of Pages:	14
Page Range:	pp. 192-205
DOI:	10.1016/j.neuropharm.2015.03.006
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	Warwick Impact Fund, University of Warwick Research Development Fund, Birmingham Science City, Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC)
Grant number:	BB/ G01227X/1 (BBSRC)

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