Multimodal single-cell sequencing of the human cortex reveals neuronal vulnerability and activated glial cell states in focal cortical dysplasia

Abstract

The role of the diverse brain cell types in focal cortical dysplasia (FCD) development and epileptogenicity is not fully understood. Here, we performed multi-omics single-cell sequencing to characterize the chromatin accessibility and transcriptomes of cortical lesions and non-lesion areas from individuals with FCD IIa and IIb, the most prevalent presentations of this neurodevelopmental disorder. Our integrative analyses of the multimodal cell atlas, encompassing 61,525 nuclei with paired open chromatin and gene expression, uncovered a selective loss of upper-layer excitatory neurons and identified a lesion-specific population expressing NEFM, a neurofilament associated with dysmorphic neurons. In glial compartments, we observed a shift towards immature astrocytic populations exhibiting features of reactive astrocytes and balloon cells. Moreover, we identified activated microglial cell states emerging in FCD IIb, indicating that neuroinflammation contributes to FCD pathogenesis. This multimodal cell atlas is a valuable resource for exploring the cellular landscape and informing novel therapeutic approaches for cortical malformations.