Cell-type-resolved transcriptomic landscape of human focal cortical dysplasia

Area of Science:

• Neuroscience
• Genomics
• Molecular Biology

Background:

• Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy.
• Significant clinical and histopathological heterogeneity exists in FCD, but its cellular and molecular underpinnings are not well understood.

Purpose of the Study:

• To create a cell-type-resolved transcriptomic atlas of human FCD.
• To identify shared and subtype-specific molecular alterations across different FCD types.

Main Methods:

• Single-nucleus RNA sequencing was performed on 487,286 nuclei from 34 paired FCD lesional cores and perilesional cortices (FCD I-III).
• Comparative transcriptomic analyses were conducted across neuronal, glial, and vascular cell types.

Main Results:

• Shared and subtype-specific transcriptional changes were identified in neurons, glia, and vascular cells.
• Inhibitory interneurons and deep-layer projection neurons showed significant dysregulation.
• Astrocytes and vascular cells exhibited coordinated activation of inflammatory, metabolic, and hypoxia pathways.
• Specific genes like ZNF254, DRG1, ABHD17A (astrocytes), and ATF4 (endothelial cells) showed subtype-associated expression.

Conclusions:

• Cell-type-specific transcriptional programs correlate with FCD histopathological heterogeneity.
• Identified potential tissue-detectable markers for FCD subtypes.
• Highlighted the role of nonneuronal cells in epileptogenic cortical malformations.