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

Celia Lentini; Marie  d’Orange; Nicolas Marichal Negrin; Marie-Madeleine Trottmann; Rory Vignoles; Louis Foucault; Charlotte Verrier; Celine Massera; Olivier Raineteau; Karl-Klaus Conzelmann; Sylvie Rival-Gervier; Antoine Depaulis; Benedikt Berninger; Christophe Heinrich

doi:10.1016/j.stem.2021.09.002

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

Celia Lentini, Marie d’Orange, Nicolas Marichal Negrin, Marie-Madeleine Trottmann, Rory Vignoles, Louis Foucault, Charlotte Verrier, Celine Massera, Olivier Raineteau, Karl-Klaus Conzelmann, Sylvie Rival-Gervier, Antoine Depaulis, Benedikt Berninger, Christophe Heinrich

Developmental Neurobiology

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Abstract

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.

Original language	English
Pages (from-to)	2104-2121.e10
Journal	Cell Stem Cell
Volume	28
Issue number	12
Early online date	29 Sept 2021
DOIs	https://doi.org/10.1016/j.stem.2021.09.002
Publication status	Published - 2 Dec 2021

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10.1016/j.stem.2021.09.002

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https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00378-7Licence: CC BY

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Lentini, C., d’Orange, M., Marichal Negrin, N., Trottmann, M.-M., Vignoles, R., Foucault, L., Verrier, C., Massera, C., Raineteau, O., Conzelmann, K.-K., Rival-Gervier, S., Depaulis, A., Berninger, B., & Heinrich, C. (2021). Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy. Cell Stem Cell, 28(12), 2104-2121.e10. https://doi.org/10.1016/j.stem.2021.09.002

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title = "Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy",

abstract = "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.",

author = "Celia Lentini and Marie d{\textquoteright}Orange and {Marichal Negrin}, Nicolas and Marie-Madeleine Trottmann and Rory Vignoles and Louis Foucault and Charlotte Verrier and Celine Massera and Olivier Raineteau and Karl-Klaus Conzelmann and Sylvie Rival-Gervier and Antoine Depaulis and Benedikt Berninger and Christophe Heinrich",

note = "Funding Information: We thank Mirjam Zeisel (CRCL, Lyon) for critical reading of the manuscript, Philippe Kahane (CHU, Grenoble) for insightful discussions on MTLE-HS, Juan Burrone (King's College London) for discussion of the electrophysiological data, Magdalena G?tz (LMU, Munich) for the Ascl1- and Dlx2-plasmids, Alejandro Schinder (Instituto Leloir, Buenos Aires) for the CAG-EGFP-2A-hM3Dq plasmid, Shaoyu Ge (Stony Brook University) for the Ubi-ChR2-EGFP plasmid, and Rosa Cossart (INMED, Marseille) for sharing the GAD67-GFP mouse line. This work was supported by ANR ReprogramEpi (ANR-14-CE13-0001), LabEx CORTEX (ANR-11-LABX-0042) of Lyon University (ANR-11-IDEX-0007), FRC, FFRE, and CURE (Award ID: 262178) to C.H.; Wellcome Trust (206410/Z/17/Z) and DFG (BE 4182/8-1 and CRC1080) to B.B.; DFG (ID 118803580 and SFB 870 Z1) to K.-K.C.; and European Community's Framework Program Neurinox (FP7, 278611) to A.D. R.V. C.L. and N.M. were supported by fellowships from R?gion Rh?ne-Alpes (R.V.; ARC2 16-005489-01), LFCE (C.L.), and Human Frontier Science Program (N.M.; LT000646/2015). Conceptualization, C.H.; design of experiments, C.H. C.L. M.d'O. N.M. and B.B.; methodology, S.R.-G.; formal analysis, C.H. C.L. M.d'O. and N.M.; investigation, C.L. M.d'O. N.M. M.-M.T. R.V. C.V. C.M. and S.R.-G.; resources, K.-K.C.; writing?original draft, C.H.; writing?review & editing, C.H. C.L. M.d'O. N.M. and B.B.; visualization, C.L. M.d'O. N.M. L.F. and O.R.; supervision, C.H.; funding acquisition, C.H. A.D. and B.B. The authors declare no competing interests. Funding Information: This work was supported by ANR ReprogramEpi ( ANR-14-CE13-0001 ), LabEx CORTEX ( ANR-11-LABX-0042 ) of Lyon University ( ANR-11-IDEX-0007 ), FRC , FFRE , and CURE (Award ID: 262178 ) to C.H.; Wellcome Trust ( 206410/Z/17/Z ) and DFG ( BE 4182/8-1 and CRC1080 ) to B.B.; DFG ( ID 118803580 and SFB 870 Z1 ) to K.-K.C.; and European Community{\textquoteright}s Framework Program Neurinox ( FP7, 278611 ) to A.D. R.V., C.L., and N.M. were supported by fellowships from R{\'e}gion Rh{\^o}ne-Alpes (R.V.; ARC2 16-005489-01 ), LFCE (C.L.) , and Human Frontier Science Program (N.M.; LT000646/2015 ). Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = dec,

day = "2",

doi = "10.1016/j.stem.2021.09.002",

language = "English",

volume = "28",

pages = "2104--2121.e10",

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number = "12",

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Lentini, C, d’Orange, M, Marichal Negrin, N, Trottmann, M-M, Vignoles, R, Foucault, L, Verrier, C, Massera, C, Raineteau, O, Conzelmann, K-K, Rival-Gervier, S, Depaulis, A, Berninger, B & Heinrich, C 2021, 'Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy', Cell Stem Cell, vol. 28, no. 12, pp. 2104-2121.e10. https://doi.org/10.1016/j.stem.2021.09.002

TY - JOUR

T1 - Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy

AU - Lentini, Celia

AU - d’Orange, Marie

AU - Marichal Negrin, Nicolas

AU - Trottmann, Marie-Madeleine

AU - Vignoles, Rory

AU - Foucault, Louis

AU - Verrier, Charlotte

AU - Massera, Celine

AU - Raineteau, Olivier

AU - Conzelmann, Karl-Klaus

AU - Rival-Gervier, Sylvie

AU - Depaulis, Antoine

AU - Berninger, Benedikt

AU - Heinrich, Christophe

N1 - Funding Information: We thank Mirjam Zeisel (CRCL, Lyon) for critical reading of the manuscript, Philippe Kahane (CHU, Grenoble) for insightful discussions on MTLE-HS, Juan Burrone (King's College London) for discussion of the electrophysiological data, Magdalena G?tz (LMU, Munich) for the Ascl1- and Dlx2-plasmids, Alejandro Schinder (Instituto Leloir, Buenos Aires) for the CAG-EGFP-2A-hM3Dq plasmid, Shaoyu Ge (Stony Brook University) for the Ubi-ChR2-EGFP plasmid, and Rosa Cossart (INMED, Marseille) for sharing the GAD67-GFP mouse line. This work was supported by ANR ReprogramEpi (ANR-14-CE13-0001), LabEx CORTEX (ANR-11-LABX-0042) of Lyon University (ANR-11-IDEX-0007), FRC, FFRE, and CURE (Award ID: 262178) to C.H.; Wellcome Trust (206410/Z/17/Z) and DFG (BE 4182/8-1 and CRC1080) to B.B.; DFG (ID 118803580 and SFB 870 Z1) to K.-K.C.; and European Community's Framework Program Neurinox (FP7, 278611) to A.D. R.V. C.L. and N.M. were supported by fellowships from R?gion Rh?ne-Alpes (R.V.; ARC2 16-005489-01), LFCE (C.L.), and Human Frontier Science Program (N.M.; LT000646/2015). Conceptualization, C.H.; design of experiments, C.H. C.L. M.d'O. N.M. and B.B.; methodology, S.R.-G.; formal analysis, C.H. C.L. M.d'O. and N.M.; investigation, C.L. M.d'O. N.M. M.-M.T. R.V. C.V. C.M. and S.R.-G.; resources, K.-K.C.; writing?original draft, C.H.; writing?review & editing, C.H. C.L. M.d'O. N.M. and B.B.; visualization, C.L. M.d'O. N.M. L.F. and O.R.; supervision, C.H.; funding acquisition, C.H. A.D. and B.B. The authors declare no competing interests. Funding Information: This work was supported by ANR ReprogramEpi ( ANR-14-CE13-0001 ), LabEx CORTEX ( ANR-11-LABX-0042 ) of Lyon University ( ANR-11-IDEX-0007 ), FRC , FFRE , and CURE (Award ID: 262178 ) to C.H.; Wellcome Trust ( 206410/Z/17/Z ) and DFG ( BE 4182/8-1 and CRC1080 ) to B.B.; DFG ( ID 118803580 and SFB 870 Z1 ) to K.-K.C.; and European Community’s Framework Program Neurinox ( FP7, 278611 ) to A.D. R.V., C.L., and N.M. were supported by fellowships from Région Rhône-Alpes (R.V.; ARC2 16-005489-01 ), LFCE (C.L.) , and Human Frontier Science Program (N.M.; LT000646/2015 ). Publisher Copyright: © 2021 The Author(s)

PY - 2021/12/2

Y1 - 2021/12/2

N2 - 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.

AB - 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.

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U2 - 10.1016/j.stem.2021.09.002

DO - 10.1016/j.stem.2021.09.002

M3 - Article

SN - 1934-5909

VL - 28

SP - 2104-2121.e10

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 12

ER -

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

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