Authors

Célia Lentini,1 Marie d’Orange,1,8 Nicolás Marichal,2,3,8 Marie-Madeleine Trottmann,1 Rory Vignoles,1 Louis Foucault,1 Charlotte Verrier,1 Céline Massera,4 Olivier Raineteau,1 Karl-Klaus Conzelmann,5 Sylvie Rival-Gervier,6 Antoine Depaulis,4 Benedikt Berninger,2,3,7 and Christophe Heinrich1,9,∗

Affiliations

"1Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, 69500 Bron, France
2Centre for Developmental Neurobiology, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London SE1 1UL, UK
3MRC Centre for Neurodevelopmental Disorders, King’s College London, London SE1 1UL, UK
4Univ Grenoble Alpes, Inserm U1216, Grenoble Institut des Neurosciences, 38000 Grenoble, France
5Max von Pettenkofer-Institute Virology, Medical Faculty & Gene Center, Ludwig-Maximilians-University, 81377 Munich, Germany
6Univ Lyon, Université Claude Bernard Lyon 1, Inserm, INRAE, Stem Cell and Brain Research Institute U1208, CSC USC1361, 69500 Bron, France
7Institute of Physiological Chemistry, University Medical Center, Johannes Gutenberg University, 55128 Mainz, Germany
Christophe Heinrich: [email protected]
∗Corresponding author [email protected]
8These authors contributed equally
9Lead contact"

Topic

Neuroscience, Optogenetics

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.

Keywords: direct lineage reprogramming, glia-to-neuron conversion, regeneration and repair in the nervous system, regenerative medicine, gene therapy, therapy-resistant epilepsy

DOI: https://dx.doi.org/ 10.1016/j.mtbio.2021.100175

Extract

iNs were visually identified on the basis of their fluorescence emission: DSRED+ (Ascl1/Dlx2) and GFP+ (ChR2, see below) using appropriate LED excitation (CoolLED pE-100) and emission filters, and were selected according to their neuronal morphology.

Product Associated Features

The compact, single-bandwidth pE-100 is ideal for visualising a single fluorophore - in this case tdT to identify dopaminergic neurons.

Product Type

pE-100

Journal

Cell stem cell

Year of Publication

2021

Country of Publication

USA