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.

将大脑驻留的神经胶质细胞重新编程为临床相关的诱导神经元 (iN) 是一种新兴的策略，用于替代丢失的神经元和恢复丢失的大脑功能。现在的一个基本问题是 iNs 是否可以促进病理情况下的功能恢复。我们在治疗抵抗性内侧颞叶癫痫 (MTLE) 的背景下解决了这个问题，这与海马癫痫发作和海马 GABA 能中间神经元的退化有关。使用 MTLE 小鼠模型，我们显示逆转录病毒驱动的 Ascl1 和 Dlx2 在反应性海马胶质细胞中的原位表达，或在癫痫海马中移植的皮质星形胶质细胞中，导致有效重编程为 iNs，显示出中间神经元的特征。这些诱导的中间神经元在功能上整合到癫痫网络中，并在齿状颗粒细胞上建立 GABA 能突触。具有 GABAergic iNs 的 MTLE 小鼠显示自发性复发性海马癫痫发作的数量和累积持续时间均显着减少。因此，神经胶质到神经元的重编程是一种潜在的疾病修饰策略，可减少难治性癫痫的癫痫发作。