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dc.contributor.authorProkic, EJen
dc.contributor.authorWeston, Cen
dc.contributor.authorYamawaki, Nen
dc.contributor.authorHall, SDen
dc.contributor.authorJones, RSGen
dc.contributor.authorStanford, IMen
dc.contributor.authorLadds, Gen
dc.contributor.authorWoodhall, GLen
dc.date.accessioned2018-02-14T10:52:36Z
dc.date.available2018-02-14T10:52:36Z
dc.date.issued2015-08en
dc.identifier.urihttp://hdl.handle.net/10026.1/10771
dc.description.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.

en
dc.format.extent192 - 205en
dc.languageengen
dc.language.isoengen
dc.subjectBeta oscillationsen
dc.subjectFast spiking interneuronsen
dc.subjectGABA(A) receptorsen
dc.subjectMotor cortexen
dc.subjectTonic currenten
dc.subjectZolpidemen
dc.subjectAction Potentialsen
dc.subjectAnimalsen
dc.subjectBeta Rhythmen
dc.subjectDose-Response Relationship, Drugen
dc.subjectFlumazenilen
dc.subjectGABA Modulatorsen
dc.subjectGABA-A Receptor Agonistsen
dc.subjectInhibitory Postsynaptic Potentialsen
dc.subjectInterneuronsen
dc.subjectKineticsen
dc.subjectMaleen
dc.subjectModels, Neurologicalen
dc.subjectPatch-Clamp Techniquesen
dc.subjectPyramidal Cellsen
dc.subjectPyridinesen
dc.subjectRats, Wistaren
dc.subjectReceptors, GABA-Aen
dc.subjectTissue Culture Techniquesen
dc.subjectZolpidemen
dc.subjectgamma-Aminobutyric Aciden
dc.titleCortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons.en
dc.typeJournal Article
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/25797493en
plymouth.volume95en
plymouth.publication-statusPublisheden
plymouth.journalNeuropharmacologyen
dc.identifier.doi10.1016/j.neuropharm.2015.03.006en
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/00 Groups by role
plymouth.organisational-group/Plymouth/00 Groups by role/Academics
plymouth.organisational-group/Plymouth/Faculty of Health and Human Sciences
plymouth.organisational-group/Plymouth/Faculty of Health and Human Sciences/School of Psychology
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA04 Psychology, Psychiatry and Neuroscience
plymouth.organisational-group/Plymouth/Research Groups
plymouth.organisational-group/Plymouth/Research Groups/Centre for Brain, Cognition and Behaviour (CBCB)
dc.publisher.placeEnglanden
dcterms.dateAccepted2015-03-08en
dc.identifier.eissn1873-7064en
dc.rights.embargoperiodNot knownen
rioxxterms.versionofrecord10.1016/j.neuropharm.2015.03.006en
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-08en
rioxxterms.typeJournal Article/Reviewen


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