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

Research output: Contribution to journalArticle

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.
LanguageEnglish
Pages192–205
Number of pages14
JournalNeuropharmacology
Volume95
Early online date20 Mar 2015
DOIs
Publication statusPublished - Aug 2015

Fingerprint

Interneurons
Benzodiazepines
GABA-A Receptors
Flumazenil
Inhibitory Postsynaptic Potentials
zolpidem
Motor Cortex
gamma-Aminobutyric Acid
Binding Sites
Brain

Bibliographical note

© 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).

Keywords

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

Cite this

Prokic, Emma J. ; Weston, Cathryn ; Yamawaki, Naoki ; Hall, Stephen D. ; Jones, Roland S.G. ; Stanford, Ian M. ; Ladds, Graham ; Woodhall, Gavin L. / Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons. In: Neuropharmacology. 2015 ; Vol. 95. pp. 192–205.
@article{156c24a9b76846ebab5115ab77ce74aa,
title = "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.",
keywords = "GABAA receptors, beta oscillations, tonic current, zolpidem, fast spiking interneurons, motor cortex",
author = "Prokic, {Emma J.} and Cathryn Weston and Naoki Yamawaki and Hall, {Stephen D.} and Jones, {Roland S.G.} and Stanford, {Ian M.} and Graham Ladds and Woodhall, {Gavin L.}",
note = "{\circledC} 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).",
year = "2015",
month = "8",
doi = "10.1016/j.neuropharm.2015.03.006",
language = "English",
volume = "95",
pages = "192–205",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier",

}

Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons. / Prokic, Emma J.; Weston, Cathryn; Yamawaki, Naoki; Hall, Stephen D.; Jones, Roland S.G.; Stanford, Ian M.; Ladds, Graham; Woodhall, Gavin L.

In: Neuropharmacology, Vol. 95, 08.2015, p. 192–205.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons

AU - Prokic, Emma J.

AU - Weston, Cathryn

AU - Yamawaki, Naoki

AU - Hall, Stephen D.

AU - Jones, Roland S.G.

AU - Stanford, Ian M.

AU - Ladds, Graham

AU - Woodhall, Gavin L.

N1 - © 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).

PY - 2015/8

Y1 - 2015/8

N2 - 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.

AB - 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.

KW - GABAA receptors

KW - beta oscillations

KW - tonic current

KW - zolpidem

KW - fast spiking interneurons

KW - motor cortex

UR - http://www.scopus.com/inward/record.url?scp=84926005809&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2015.03.006

DO - 10.1016/j.neuropharm.2015.03.006

M3 - Article

VL - 95

SP - 192

EP - 205

JO - Neuropharmacology

T2 - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -