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

Abstract

Focal cortical dysplasia (FCD) is a major cause of drug-resistant epilepsy and displays substantial clinical and histopathological heterogeneity, yet the cellular and molecular bases underlying this diversity remain poorly defined. Here, we performed single-nucleus RNA sequencing of 487,286 nuclei from 34 paired lesional cores and perilesional cortices across FCD I-III, generating a cell-type-resolved transcriptomic atlas of human FCD. Comparative analyses identified both shared and subtype-specific transcriptional alterations across neuronal, glial, and vascular compartments. Inhibitory interneurons and deep-layer projection neurons exhibited prominent dysregulation, whereas astrocytes and vascular cells showed coordinated activation of inflammatory, metabolic, and hypoxia-responsive pathways. Several genes displayed consistent subtype-associated expression patterns, including <i>ZNF254</i>, <i>DRG1</i>, and <i>ABHD17A</i> in astrocytes, and <i>ATF4</i> in endothelial cells. These results link cell-type-specific transcriptional programs to histopathological heterogeneity across FCD subtypes, identify candidate tissue-detectable markers, and provide insight into nonneuronal contributions to epileptogenic cortical malformations.