title: Control of Inhibition by the Direct Action of Cannabinoids on GABAA Receptors.
abstract: Cannabinoids are known to regulate inhibitory synaptic transmission via activation of presynaptic G protein-coupled cannabinoid CB1 receptors (CB1Rs). Additionally, recent studies suggest that cannabinoids can also directly interact with recombinant GABAA receptors (GABAARs), potentiating currents activated by micromolar concentrations of γ-aminobutyric acid (GABA). However, the impact of this direct interaction on GABAergic inhibition in central nervous system is unknown. Here we report that currents mediated by recombinant GABAARs activated by high (synaptic) concentrations of GABA as well as GABAergic inhibitory postsynaptic currents (IPSCs) at neocortical fast spiking (FS) interneuron to pyramidal neuron synapses are suppressed by exogenous and endogenous cannabinoids in a CB1R-independent manner. This IPSC suppression may account for disruption of inhibitory control of pyramidal neurons by FS interneurons. At FS interneuron to pyramidal neuron synapses, endocannabinoids induce synaptic low-pass filtering of GABAAR-mediated currents evoked by high-frequency stimulation. The CB1R-independent suppression of inhibition is synapse specific. It does not occur in CB1R containing hippocampal cholecystokinin-positive interneuron to pyramidal neuron synapses. Furthermore, in contrast to synaptic receptors, the activity of extrasynaptic GABAARs in neocortical pyramidal neurons is enhanced by cannabinoids in a CB1R-independent manner. Thus, cannabinoids directly interact differentially with synaptic and extrasynaptic GABAARs, providing a potent novel context-dependent mechanism for regulation of inhibition.
authors.affiliation: Department of Clinical Neurobiology, University Hospital for Neurology, University of Heidelberg, 69120 Heidelberg, Germany Current Address: Research Group Computational Neuroscience, Central Institute of Mental Health, 68159 Mannheim, Germany.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Golovko
authors.affiliation: Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University, 1081 HV Amsterdam, The Netherlands Current Address: Molecular Visual Plasticity Group, Netherlands Institute for Neuroscience, 1105 BA Amsterdam, The Netherlands.
authors.forename: Rogier
authors.initials: R
authors.lastname: Min
authors.affiliation: Department of Cellular Membranology, Bogomoletz Institute of Physiology, 01204 Kiev, Ukraine INSERM U901, Institut de Neurobiologie de la Méditerranée (INMED), 13273 Marseille, France UMR901, Aix-Marseille Université, 13273 Marseille, France.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lozovaya
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee University, Dundee DD1 9SY, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Falconer
authors.affiliation: Department of Cellular Membranology, Bogomoletz Institute of Physiology, 01204 Kiev, Ukraine.
authors.forename: Natalia
authors.initials: N
authors.lastname: Yatsenko
authors.affiliation: INSERM U901, Institut de Neurobiologie de la Méditerranée (INMED), 13273 Marseille, France UMR901, Aix-Marseille Université, 13273 Marseille, France.
authors.forename: Timur
authors.initials: T
authors.lastname: Tsintsadze
authors.affiliation: INSERM U901, Institut de Neurobiologie de la Méditerranée (INMED), 13273 Marseille, France UMR901, Aix-Marseille Université, 13273 Marseille, France.
authors.forename: Vera
authors.initials: V
authors.lastname: Tsintsadze
authors.affiliation: Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles, 1050 Bruxelles, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.affiliation: Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harvey
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee University, Dundee DD1 9SY, UK.
authors.forename: Delia
authors.initials: D
authors.lastname: Belelli
authors.affiliation: Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee University, Dundee DD1 9SY, UK.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Lambert
authors.affiliation: Department of Clinical Neurobiology, University Hospital for Neurology, University of Heidelberg, 69120 Heidelberg, Germany Division of Neuroscience, Medical Research Institute, Ninewells Hospital and Medical School, Dundee University, Dundee DD1 9SY, UK Laboratory of Neurobiology, Kazan Federal University, Kazan, Russia.
authors.forename: Andrei
authors.initials: A
authors.lastname: Rozov
authors.affiliation: Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, VU University, 1081 HV Amsterdam, The Netherlands INSERM U901, Institut de Neurobiologie de la Méditerranée (INMED), 13273 Marseille, France UMR901, Aix-Marseille Université, 13273 Marseille, France.
authors.forename: Nail
authors.initials: N
authors.lastname: Burnashev
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002186:Cannabinoids / Q000378:metabolism* / Q000494:pharmacology; D018682:GABA Agents / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D018079:Receptors, GABA / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D014162:Transfection
chemical_list: D002186:Cannabinoids; D018682:GABA Agents; D043884:Receptor, Cannabinoid, CB1; D018079:Receptors, GABA
keywords: CB1 receptors; DSI; endocannabinoids; fast-spiking interneurons; inhibitory synaptic transmission; neocortex