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The Journal of Neuroscience, December 19, 2007, 27(51):14108-14116; doi:10.1523/JNEUROSCI.2618-07.2007

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Neurobiology of Disease
GABA_A Receptor 2 Subunit Mutations Linked to Human Epileptic Syndromes Differentially Affect Phasic and Tonic Inhibition

Emmanuel Eugène,^1,2 Christel Depienne,^2,3 Stéphanie Baulac,^2,3 Michel Baulac,^1,2,4 Jean Marc Fritschy,⁵ Eric Le Guern,^2,3 Richard Miles,^1,2 and Jean Christophe Poncer^1,2,6

¹Inserm, Unité 739, 75013 Paris, France, ²Université Pierre et Marie Curie-Paris 6, Institut Fédératif de Recherche 70, 75013 Paris, France, ³Inserm, Unité 679, 75013 Paris, France, ⁴Assistance Publ Hop Paris, Hopital Pitié Salpétrière, Service de Neurologie, 75013 Paris, France, ⁵Institute for Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland, and ⁶Inserm, Unité 839, 75005 Paris, France

Correspondence should be addressed to Jean Christophe Poncer, Inserm, Unité 839, Avenir Team "Plasticity in Cortical Networks and Epilepsy," Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France. Email: poncer{at}fer-a-moulin.inserm.fr

GABA acts on GABA_A receptors to evoke both phasic inhibitory synaptic events and persistent, tonic currents. The 2 subunit of the GABA_A receptor is involved in both phasic and tonic signaling in the hippocampus. Several mutations of this subunit are linked to human epileptic syndromes with febrile seizures, yet it is not clear how they perturb neuronal activity. Here, we examined the expression and functional impact of recombinant 2 in hippocampal neurons. We show that the K289M mutation has no effect on membrane trafficking and synaptic aggregation of recombinant 2, but accelerates the decay of synaptic currents. In contrast, the R43Q mutation primarily reduces surface expression of recombinant 2. However, it has no dominant effect on synaptic currents but instead reduces tonic GABA currents, at least in part by reducing surface expression of the 5 subunit. Our data suggests that the phenotypic specificity of mutations affecting the GABA_A receptor 2 gene may result from different actions specific to distinct modes of GABAergic signaling.

Key words: GABA; GABA_A receptor; epilepsy; hippocampus; synaptic transmission; benzodiazepine

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Received June 8, 2007; revised Nov. 2, 2007; accepted Nov. 2, 2007.

Correspondence should be addressed to Jean Christophe Poncer, Inserm, Unité 839, Avenir Team "Plasticity in Cortical Networks and Epilepsy," Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France. Email: poncer{at}fer-a-moulin.inserm.fr

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