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.
authors: Aston Brain Centre, Aston University, School of Life and Health Sciences, Birmingham, B4 7ET, UK.
authors: Emma J
authors: EJ
authors: Prokic
authors: Division of Biomedical Cell Biology, University of Warwick Medical School, Coventry, CV4 7AL, UK.
authors: Cathryn
authors: C
authors: Weston
authors: Aston Brain Centre, Aston University, School of Life and Health Sciences, Birmingham, B4 7ET, UK.
authors: Naoki
authors: N
authors: Yamawaki
authors: Aston Brain Centre, Aston University, School of Life and Health Sciences, Birmingham, B4 7ET, UK.
authors: Stephen D
authors: SD
authors: Hall
authors: Department of Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
authors: Roland S G
authors: RS
authors: Jones
authors: Aston Brain Centre, Aston University, School of Life and Health Sciences, Birmingham, B4 7ET, UK.
authors: Ian M
authors: IM
authors: Stanford
authors: Division of Biomedical Cell Biology, University of Warwick Medical School, Coventry, CV4 7AL, UK. Electronic address: Graham.Ladds@warwick.ac.uk.
authors: Graham
authors: G
authors: Ladds
authors: Aston Brain Centre, Aston University, School of Life and Health Sciences, Birmingham, B4 7ET, UK. Electronic address: G.L.Woodhall@aston.ac.uk.
authors: Gavin L
authors: GL
authors: Woodhall
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001611:Beta Rhythm / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007395:Interneurons / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D008297:Male; D008959:Models, Neurological; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D046509:Tissue Culture Techniques; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D011725:Pyridines; D011963:Receptors, GABA-A; D005442:Flumazenil; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem
keywords: Beta oscillations; Fast spiking interneurons; GABA(A) receptors; Motor cortex; Tonic current; Zolpidem