Multimodal single-cell analyses reveal molecular markers of neuronal senescence in human drug-resistant epilepsy
The histopathological neurons in the brain tissue of drug-resistant epilepsy exhibit aberrant cytoarchitecture and imbalanced synaptic circuit function. However, the gene expression changes of these neurons remain unknown, making it difficult to determine the diagnosis or to dissect the mechanism of drug-resistant epilepsy. By integrating whole-cell patch clamp recording and single-cell RNA-seq approaches, we identified a transcriptionally distinct subset of cortical pyramidal neurons. These neurons highly expressed genes CDKN1A (P21), CCL2, and NFKBIA, which associate with mTOR pathway, inflammatory response, and cellular senescence. We confirmed the expression of senescent marker genes in a subpopulation of cortical pyramidal neurons with enlarged soma size in the brain tissue of drug-resistant epilepsy. We further revealed the expression of senescent cell markers P21, P53, COX2, γ-H2AX, and β-Gal, and reduction of nuclear integrity marker Lamin B1 in histopathological neurons in the brain tissue of patients with drug-resistant epilepsy with different pathologies, but not in control brain tissue with no history of epilepsy. Additionally, chronic, but not acute, epileptic seizures induced senescent marker expression in cortical neurons in mouse models of drug-resistant epilepsy. These results provide important molecular markers for histopathological neurons and what we believe to be new insights into the pathophysiological mechanisms of drug-resistant epilepsy.
Authors
- Shumin Duan (ORCID: https://orcid.org/0000-0002-0466-1821)
- Suixin Deng (ORCID: https://orcid.org/0000-0003-4795-2570)
- Mengyue Zhu
- Jingxin Guo (ORCID: https://orcid.org/0000-0002-3099-7900)
- Yi Wang (ORCID: https://orcid.org/0000-0002-1350-2961)
- Xinyue Dai (ORCID: https://orcid.org/0000-0001-8684-2118)
- Qianqian Ge (ORCID: https://orcid.org/0000-0003-4862-0615)
- Ying Shen (ORCID: https://orcid.org/0000-0002-3220-904X)
- Fei Huang (ORCID: https://orcid.org/0000-0002-2795-3114)
- Jiachao Yang
- Zhong Chen (ORCID: https://orcid.org/0000-0003-4755-9357)
- Jianmin Zhang (ORCID: https://orcid.org/0000-0001-6005-1270)
- Junming Zhu (ORCID: https://orcid.org/0000-0002-2781-3306)
- Chao Chen (ORCID: https://orcid.org/0000-0003-0789-7749)
- Li Shen (ORCID: https://orcid.org/0000-0002-5696-2191)
- Mi Wang (ORCID: https://orcid.org/0000-0001-8804-7417)
- Huiying Zhang (ORCID: https://orcid.org/0000-0002-5528-4712)
- Yu Zhou (ORCID: https://orcid.org/0000-0002-1407-6140)
- Xiaoqun Wang (ORCID: https://orcid.org/0000-0003-3440-2617)
- Shengjin Xu (ORCID: https://orcid.org/0000-0002-2388-3446)
- Jiadong Chen (ORCID: https://orcid.org/0000-0002-4915-5682)
- Yijie Shao
- Yiqi Hu
- Jieqiao Peng
- Jiachen Shi (ORCID: https://orcid.org/0000-0002-2247-8449)
- Yuxian Xia
- Xiao-ming Li
- Yousheng Shu
Institutions
- Zhejiang Chinese Medical University (CN)
- Allen Institute for Brain Science (US)
- Chinese Academy of Sciences (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Fudan University (CN)
- Beijing Normal University (CN)
- Center for Excellence in Brain Science and Intelligence Technology (CN)
- Chinese Institute for Brain Research (CN)
- Zhejiang Lab (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Huashan Hospital (CN)
- Shanghai Center for Brain Science and Brain-Inspired Technology (CN)
- University of Chinese Academy of Sciences (CN)
- State Key Laboratory of Medical Neurobiology
- Zhejiang University (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-03-02
- DOI
- https://doi.org/10.1172/jci188942
- Citations
- 9
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 8.18
Funders
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- Fundamental Research Funds for the Central Universities
- Natural Science Foundation of Zhejiang Province