Excitatory neurons and astrocytes-specific dysregulation and aberrant interactions are vulnerable to FCDI as suggested by single-cell spatial transcriptomics.

Overview

1. Department of Neurology, The Seventh Affiliated Hospital, Sun Yat‐Sen University, Shenzhen, China
2. Department of Neurology, Henan Provincial People' s Hospital；Zhengzhou University People' s Hospital, Zhengzhou, China
3. Department of Neurology, Third Affiliated Hospital, Sun Yat‐Sen University, Guangzhou, China
4. Department of Epilepsy Center, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
5. Department of Neurology, Epilepsy Center, Shenzhen Children's Hospital, Shenzhen, China

Abstract

Background: Focal cortical dysplasia (FCD) is a common neurodevelopmental disorder characterised by cortical malformations and is a major cause of drug‐resistant epilepsy. FCD type I (FCDI) presents with architectural abnormalities of the neocortex but without cytological abnormalities. Currently, FCDI remains a significant clinical challenge.

Methods: Epileptogenic cortical tissues from three FCDI patients and three relatively normal neocortical tissues as controls were analysed using single‐nucleus RNA sequencing and spatial transcriptomic for multi‐omics integration.

Results: This study constructed a single‐cell spatial transcriptomic atlas of the epileptogenic cortex from FCDI patients. Excitatory neurons (ENs) and astrocytes (Ast) exhibited the most prominent alterations in FCDI. Hub genes associated with FCDI were identified in ENs, and a transcription factor (TF)‒hub gene regulatory network was constructed. Notably, CBLN2 highEx‐1 was identified as being potentially involved in processes related to neuronal hyperexcitability and cortical development in FCDI. Western blot and immunofluorescence assays validated the altered expression of selected key genes and TFs at the protein level. Additionally, Ast exhibited increased heterogeneity, impaired differentiation and a higher proportion of immature Ast in FCDI, with predicted TFs regulating this process. Further analysis revealed aberrant signalling pathways and ligand‒receptor interactions between ENs and Ast in FCDI, with spatial co‐localisation patterns that may contribute to disease progression.

Conclusions: This study highlights the specific dysregulation of ENs and Ast, along with aberrant cellular communication, which may play a critical role in the pathogenesis of FCDI. These findings provide novel insights into the molecular mechanisms underlying FCDI and offer potential therapeutic targets for precision treatment and drug development.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE295236, at NCBI GEO; found in “DATA AVAILABILITY STATEMENT”

Data availability statement

The RNA‐seq and ST‐seq datasets (FASTQ files) and processed data during the current study were deposited in GEO under accession numbers GSE295236 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295236) and GSE295237 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE295237).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 5 keywords, 6 MeSH terms, 2 funders, 132 references.

Cite

This paper

Zhang, Y., Zou, Q., Liu, Y., Li, Y., Fang, Y., Huang, T., Yu, J., Sui, L., Cao, D., & Zhou, L. (2026). Excitatory neurons and astrocytes-specific dysregulation and aberrant interactions are vulnerable to FCDI as suggested by single-cell spatial transcriptomics. Clinical and translational medicine, 16(5), e70673. https://doi.org/10.1002/ctm2.70673

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