Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy
In: Cell Stem Cell Cell Stem Cell, Cambridge, MA : Cell Press, 2021, ⟨10.1016/j.stem.2021.09.002⟩ Cell Stem Cell, 2021, 28 (12), pp.2104-2121.e10. ⟨10.1016/j.stem.2021.09.002⟩; (2021-09-01)
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Zugriff:
Summary 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.
Graphical abstract
Highlights • Retroviruses target reactive hippocampal glia proliferating in a mouse model of mesial temporal lobe epilepsy • Ascl1 and Dlx2 reprogram reactive glia into GABAergic interneurons in the epileptic hippocampus • Induced interneurons establish GABAergic synapses onto dentate granule cells • Induced interneurons reduce chronic epileptic activity in the hippocampus
Mesial temporal lobe epilepsy belongs to treatment-refractory forms of human epilepsy. Lentini et al. show that reactive glia proliferating in the epileptic hippocampus can be reprogrammed into GABAergic induced neurons that reduce chronic seizure activity. This study uncovers glia-to-neuron reprogramming as a potential disease-modifying strategy to reduce intractable seizures.
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Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy
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| Autor/in / Beteiligte Person: | Conzelmann, Karl-Klaus ; Marichal, Nicolás ; Verrier, Charlotte ; Raineteau, Olivier ; Vignoles, Rory ; Rival-Gervier, Sylvie ; Depaulis, Antoine ; Foucault, Louis ; Heinrich, Christophe ; Trottmann, Marie-Madeleine ; d’Orange, Marie ; Lentini, Célia ; Berninger, Benedikt ; Massera, Céline ; Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (U1208 Inserm - UCBL1 / SBRI - USC 1361 INRAE) ; Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE) ; King‘s College London ; Dynamique et Structure du Cytosquelette Neuronal ; [GIN] Grenoble Institut des Neurosciences (GIN) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA) ; Ludwig-Maximilians University [Munich] (LMU) ; Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (SBRI) ; Institute of Psychiatry, Psychology & Neuroscience, King's College London ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA) ; Max Von Pettenkofer Institute (MVP) ; Ludwig-Maximilians-Universität München (LMU) ; University Medical Center of the Johannes Gutenberg-University Mainz ; 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). ; ANR-14-CE13-0001,ReprogramEpi,La reprogrammation des astrocytes réactionnels en neurones GABAergiques: une nouvelle approche thérapeutique de l'épilepsie(2014) ; ANR-11-LABX-0042,CORTEX,Construction, Fonction Cognitive et Réhabilitation du Cerveau(2011) ; ANR-11-IDEX-0007,Avenir L.S.E.,PROJET AVENIR LYON SAINT-ETIENNE(2011) ; European Project: 278611,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,NEURINOX(2012) ; heinrich, christophe ; Appel à projets générique - La reprogrammation des astrocytes réactionnels en neurones GABAergiques: une nouvelle approche thérapeutique de l'épilepsie - - ReprogramEpi2014 - ANR-14-CE13-0001 - Appel à projets générique -, VALID ; Construction, Fonction Cognitive et Réhabilitation du Cerveau - - CORTEX2011 - ANR-11-LABX-0042 - LABX - VALID ; PROJET AVENIR LYON SAINT-ETIENNE - - Avenir L.S.E.2011 - ANR-11-IDEX-0007 - IDEX -, VALID ; NOX enzymes as mediators of inflammation-triggered neurodegeneration: modulating NOX enzymes as novel therapies - NEURINOX - - EC:FP7:HEALTH2012-01-01 - 2016-12-31 - 278611 -, VALID ; Institut cellule souche et cerveau (U846 Inserm - UCBL1) ; Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM) |
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| Quelle: | Cell Stem Cell Cell Stem Cell, Cambridge, MA : Cell Press, 2021, ⟨10.1016/j.stem.2021.09.002⟩ Cell Stem Cell, 2021, 28 (12), pp.2104-2121.e10. ⟨10.1016/j.stem.2021.09.002⟩; (2021-09-01) |
| Veröffentlichung: | HAL CCSD, 2021 |
| Medientyp: | unknown |
| ISSN: | 1934-5909 (print) ; 1875-9777 (print) |
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