Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy.

Autor:	Lentini C; Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France., d'Orange M; Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France., Marichal N; Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE1 1UL, UK; MRC Centre for Neurodevelopmental Disorders, King's College London, London SE1 1UL, UK., Trottmann MM; Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France., Vignoles R; Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France., Foucault L; Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France., Verrier C; Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France., Massera C; Univ Grenoble Alpes, Inserm U1216, Grenoble Institut des Neurosciences, 38000 Grenoble, France., Raineteau O; Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France., Conzelmann KK; Max von Pettenkofer-Institute Virology, Medical Faculty & Gene Center, Ludwig-Maximilians-University, 81377 Munich, Germany., Rival-Gervier S; Univ Lyon, Université Claude Bernard Lyon 1, Inserm, INRAE, Stem Cell and Brain Research Institute U1208, CSC USC1361, 69500 Bron, France., Depaulis A; Univ Grenoble Alpes, Inserm U1216, Grenoble Institut des Neurosciences, 38000 Grenoble, France., Berninger B; Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE1 1UL, UK; MRC Centre for Neurodevelopmental Disorders, King's College London, London SE1 1UL, UK; Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, 55128 Mainz, Germany., Heinrich C; Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France. Electronic address: christophe.heinrich@inserm.fr.
Jazyk:	angličtina
Zdroj:	Cell stem cell [Cell Stem Cell] 2021 Dec 02; Vol. 28 (12), pp. 2104-2121.e10. Date of Electronic Publication: 2021 Sep 29.
DOI:	10.1016/j.stem.2021.09.002
Abstrakt:	Reprogramming brain-resident glial cells into clinically relevant induced neurons (iNs) is an emerging strategy toward replacing lost neurons and restoring lost brain functions. A fundamental question is now whether iNs can promote functional recovery in pathological contexts. We addressed this question in the context of therapy-resistant mesial temporal lobe epilepsy (MTLE), which is associated with hippocampal seizures and degeneration of hippocampal GABAergic interneurons. Using a MTLE mouse model, we show that retrovirus-driven expression of Ascl1 and Dlx2 in reactive hippocampal glia in situ, or in cortical astroglia grafted in the epileptic hippocampus, causes efficient reprogramming into iNs exhibiting hallmarks of interneurons. These induced interneurons functionally integrate into epileptic networks and establish GABAergic synapses onto dentate granule cells. MTLE mice with GABAergic iNs show a significant reduction in both the number and cumulative duration of spontaneous recurrent hippocampal seizures. Thus glia-to-neuron reprogramming is a potential disease-modifying strategy to reduce seizures in therapy-resistant epilepsy. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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