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

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. [Display omitted] •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.