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LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels

Michael Seagar 1 Michaël Russier 1 Olivier Caillard 1 Yves Maulet 1 Laure Fronzaroli-Molinieres 1 Marina de San Feliciano 1 Norah Boumedine-Guignon 1 Léa Rodriguez 1 Mickael Zbili 1 Fabrice Usseglio 1 Christine Formisano-Tréziny 1 Fahamoe Youssouf 1 Marion Sangiardi 1 Morgane Boillot 2 Stéphanie Baulac 2 Maria Jose Benitez 3, 4 Juan-José Garrido 4 Dominique Debanne 1 Oussama El Far 1
1 UNIS - Inserm U1072 - Unité de Neurobiologie des canaux Ioniques et de la Synapse
2 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
3 UAM - Universidad Autonoma de Madrid
4 Instituto Cajal, CSIC
Abstract : Autosomal dominant epilepsy with auditory features results from mutations in leucine-rich glioma-inactivated 1 (LGI1), a soluble glycoprotein secreted by neurons. Animal models of LGI1 depletion display spontaneous seizures, however, the function of LGI1 and the mechanisms by which deficiency leads to epilepsy are unknown. We investigated the effects of pure recombinant LGI1 and genetic depletion on intrinsic excitability, in the absence of synaptic input, in hippocampal CA3 neurons, a classical focus for epileptogenesis. Our data indicate that LGI1 is expressed at the axonal initial segment and regulates action potential firing by setting the density of the axonal Kv1.1 channels that underlie dendrotoxin-sensitive D-type potassium current. LGI1 deficiency incurs a >50% down-regulation of the expression of Kv1.1 and Kv1.2 via a posttranscriptional mechanism, resulting in a reduction in the capacity of axonal D-type current to limit glutamate release, thus contributing to epileptogenesis.
Keywords : epilepsy LGI1 intrinsic excitability D-type current Kv1 channels
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https://www.hal.inserm.fr/inserm-01708767
Contributor : Oussama El Far <>
Submitted on : Wednesday, February 14, 2018 - 9:48:47 AM
Last modification on : Thursday, December 10, 2020 - 3:44:37 AM

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Michael Seagar, Michaël Russier, Olivier Caillard, Yves Maulet, Laure Fronzaroli-Molinieres, et al.. LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2017, 114 (29), pp.7719 - 7724. ⟨10.1073/pnas.1618656114⟩. ⟨inserm-01708767⟩

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