title: GABA(B) autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice.
abstract: GABA(B) receptors (GABA(B)Rs) mediate slow inhibitory effects on neuronal excitability and synaptic transmission in the brain. However, the GABA(B)R agonist baclofen can also promote excitability and seizure generation in human patients and animals models. Here we show that baclofen has concentration-dependent effects on the hippocampal network in a mouse model of mesial temporal lobe epilepsy. Application of baclofen at a high dose (10 mg/kg i.p.) reduced the power of γ oscillations and the frequency of pathological discharges in the Cornu Ammonis area 3 (CA3) area of freely moving epileptic mice. Unexpectedly, at a lower dose (1 mg/kg), baclofen markedly increased γ activity accompanied by a higher incidence of pathological discharges. Intracellular recordings from CA3 pyramidal cells in vitro further revealed that, although at a high concentration (10 µM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 µM), the drug had divergent effects, producing depolarization and an increase in firing frequency in epileptic but not control mice. These excitatory effects were mediated by the selective muting of inhibitory cholecystokinin-positive basket cells (CCK(+) BCs), through enhanced inhibition of GABA release via presynaptic GABA(B)Rs. We conclude that cell type-specific up-regulation of GABA(B)R-mediated autoinhibition in CCK(+) BCs promotes aberrant high frequency oscillations and hyperexcitability in hippocampal networks of chronic epileptic mice.
authors: Institute of Neurophysiology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors: Tamar
authors: T
authors: Dugladze
authors: Nino
authors: N
authors: Maziashvili
authors: Christoph
authors: C
authors: Börgers
authors: Shalva
authors: S
authors: Gurgenidze
authors: Ute
authors: U
authors: Häussler
authors: Aline
authors: A
authors: Winkelmann
authors: Carola A
authors: CA
authors: Haas
authors: Jochen C
authors: JC
authors: Meier
authors: Imre
authors: I
authors: Vida
authors: Nancy J
authors: NJ
authors: Kopell
authors: Tengis
authors: T
authors: Gloveli
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000502:physiology*; D001418:Baclofen / Q000008:administration & dosage; D056654:CA3 Region, Hippocampal / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002766:Cholecystokinin / Q000378:metabolism; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D004833:Epilepsy, Temporal Lobe / Q000473:pathology / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage; D058786:GABA-B Receptor Agonists / Q000008:administration & dosage; D006801:Humans; D007608:Kainic Acid / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D008959:Models, Neurological; D009415:Nerve Net / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D018080:Receptors, GABA-B / Q000502:physiology*
chemical_list: D017660:Autoreceptors; D018690:Excitatory Amino Acid Agonists; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; D002766:Cholecystokinin; D001418:Baclofen; D007608:Kainic Acid
keywords: mTLE model; patch clamp; presynaptic inhibition
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