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Exploratory Single-Cell Transcriptomic Profiling Reveals Dysregulated Glial Populations and Pathways in Focal Cortical Dysplasia Epilepsy
by
,
Chao Jiang
1,2, 
Qingyao Gao
3,
Yan Zhao
1,
Yiming You
1,
Zhuojue Wang
4,
Jian Wang
2,5,
Guang Yang
5,6,
Chuang Guo
1,* and
Zhiqiang Cui
2,5,* 1
Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Institute of Neuroscience, Northeastern University, No. 195, Chuangxin Road, Hunnan District, Shenyang 110169, China
2
Department of Neurosurgery, Chinese People’s Liberation Army of General Hospital, 28, Fuxing Road, Haidian District, Beijing 100853, China
3
Institute of Scientific Research, National Health Commission, Beijing 100089, China
4
School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, China
5
Medical School of Chinese People’s Liberation Army, Beijing 100853, China
6
Senior Department of Pediatrics, Chinese People’s Liberation Army of General Hospital, Beijing 100700, China
*
Authors to whom correspondence should be addressed.
Biology 2025, 14(12), 1690; https://doi.org/10.3390/biology14121690
Submission received: 2 November 2025
/
Revised: 21 November 2025
/
Accepted: 26 November 2025
/
Published: 27 November 2025
Simple Summary
Focal cortical dysplasia (FCD) is a brain condition that frequently leads to severe, hard-to-treat epilepsy. The exact ways in which brain cells contribute to the development of seizures in FCD are not fully understood. In this study, we used advanced technology to analyze individual brain cells from a patient with FCD. We discovered that the brain cell environment is drastically changed, with an overabundance of specific immune cells and a major loss of other supportive cells. These altered cells share common problems, including increased inflammation and faulty energy production, which disrupts how cells talk to each other. Our exploratory findings shed light on potential mechanisms underlying seizures in FCD and highlight two specific biological pathways that could be explored for future therapeutic strategies.
Abstract
Background: Focal cortical dysplasia (FCD) is a prevalent cause of drug-resistant epilepsy, but a comprehensive understanding of its pathogenesis at a cellular resolution remains limited. Previous transcriptomic studies, often constrained by bulk tissue analysis, have been unable to dissect the cell-type-specific contributions to epileptogenesis. Methods: We performed scRNA-seq on cortical tissues from one surgical patient with FCD type II and one matched control. Cell clustering, annotation, and identification of differentially expressed genes (DEGs) were conducted using standard Seurat workflow. We focused on the molecular alterations in three major glial cell types: astrocytes, microglia, and oligodendrocytes. To functionally interpret the DEGs, we performed enrichment analyses using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Results: Our profiling revealed a profoundly reconstituted cellular ecosystem in the FCD cortex. We found a marked expansion of microglia (65.57% vs. 47.02%; a ~39% relative increase) and astrocytes (10.98% vs. 4.11%; a ~167% relative increase), alongside a severe depletion of oligodendrocytes (8.12% vs. 30.63%; a ~73% relative decrease). Critically, a core set of 128 differentially expressed genes (DEGs) was shared across these glial populations, featuring consistent upregulation of RAC1 and downregulation of ATP5F1D, pointing to convergent pro-inflammatory and mitochondrial dysfunction pathways. Enrichment analyses further demonstrated a coordinated engagement of neuroinflammatory pathways, most notably IL-17 signaling. Subsequent cell–cell communication inference revealed a broad attenuation of intercellular signaling, with a 35% reduction in interaction numbers, indicating a breakdown of coordinated cellular crosstalk. Conclusions: This exploratory single-cell study provides preliminary evidence of a convergent glial pathology in FCD, characterized by shared molecular disruptions in inflammation and metabolism. Our findings highlight RAC1 and IL-17 signaling as potentially actionable pathways, warranting further investigation into their therapeutic potential for mitigating epileptogenesis in FCD.
