Zheng Jiajun, Li Tingjie, Qi Shuang, Qin Bing, Yu Jiandong, Chen Gong
GHM Institute of CNS Regeneration, Jinan University, Guangzhou, China.
Epilepsy Center and Department of Neurosurgery, The First Affifiliated Hospital, Jinan University, Guangzhou, China.
Prog Neurobiol. 2022 Jan;208:102198. doi: 10.1016/j.pneurobio.2021.102198. Epub 2021 Nov 28.
Temporal lobe epilepsy (TLE) is a common drug-resistant epilepsy associated with abundant cell death in the hippocampus. Here, we develop a novel gene therapy-mediated cell therapy that regenerates GABAergic neurons using internal hippocampal astrocytes to suppress seizure activity in a rat TLE model. We discovered that TLE-induced reactive astrocytes in the hippocampal CA1 region can be efficiently converted into GABAergic neurons after overexpressing a neural transcription factor NeuroD1. The astrocyte-converted neurons showed typical markers of GABAergic interneurons, fired action potentials, and formed functional synaptic connections with other neurons. Following NeuroD1-mediated astrocyte-to-neuron conversion, the number of hippocampal interneurons was significantly increased, and the spontaneous recurrent seizure (SRS) activity was significantly decreased. Moreover, NeuroD1 gene therapy treatment rescued total neuronal loss in the CA1 region and ameliorated the cognitive and mood dysfunctions in the TLE rat model. These results suggest that regeneration of GABAergic interneurons through gene therapy approach may provide a novel therapeutic intervention to treat drug-resistant TLE.
颞叶癫痫（TLE）是一种常见的耐药性癫痫，与海马体中大量细胞死亡有关。在此，我们开发了一种新型的基因治疗介导的细胞疗法，利用海马体内的星形胶质细胞再生γ-氨基丁酸能神经元，以抑制大鼠TLE模型中的癫痫发作活动。我们发现，在过表达神经转录因子NeuroD1后，TLE诱导的海马CA1区反应性星形胶质细胞可有效转化为γ-氨基丁酸能神经元。星形胶质细胞转化而来的神经元表现出γ-氨基丁酸能中间神经元的典型标志物，产生动作电位，并与其他神经元形成功能性突触连接。在NeuroD1介导的星形胶质细胞向神经元转化后，海马中间神经元的数量显著增加，自发性反复癫痫发作（SRS）活动显著减少。此外，NeuroD1基因治疗挽救了CA1区的全部神经元损失，并改善了TLE大鼠模型中的认知和情绪功能障碍。这些结果表明，通过基因治疗方法再生γ-氨基丁酸能中间神经元可能为治疗耐药性TLE提供一种新的治疗干预措施。
