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GABA(B) autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice

Item Type:Article
Title:GABA(B) autoreceptor-mediated cell type-specific reduction of inhibition in epileptic mice
Creators Name:Dugladze, T. and Maziashvili, N. and Boergers, C. and Gurgenidze, S. and Haeussler, U. and Winkelmann, A. and Haas, C.A. and Meier, J.C. and Vida, I. and Kopell, N.J. and Gloveli, T.
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 gamma 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 gamma 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 microM), baclofen invariably resulted in hyperpolarization, at low concentrations (0.5 microM), 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.
Keywords:Presynaptic Inhibition, mTLE Model, Patch Clamp, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:15073-15078
Date:10 September 2013
Official Publication:https://doi.org/10.1073/pnas.1313505110
PubMed:View item in PubMed

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