Multimodal single-cell profiling reveals neuronal vulnerability and pathological cell states in focal cortical dysplasia
Isabella C. Galvão,
Manuela Lemoine,
Lauana A. Messias,
Patrícia A.O.R.A. Araújo,
Jaqueline C. Geraldis,
Clarissa L. Yasuda,
Marina K.M. Alvim,
Enrico Ghizoni,
Helder Tedeschi,
Fernando Cendes,
Fabio Rogerio,
Iscia Lopes-Cendes,
Diogo F.T. Veiga
Affiliations
Isabella C. Galvão
Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), São Paulo, Brazil; The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil
Manuela Lemoine
Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), São Paulo, Brazil; The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil
Lauana A. Messias
Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), São Paulo, Brazil; The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil
Patrícia A.O.R.A. Araújo
Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), São Paulo, Brazil; The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil
Jaqueline C. Geraldis
Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), São Paulo, Brazil; The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil
Clarissa L. Yasuda
The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil; Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
Marina K.M. Alvim
The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil; Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
Enrico Ghizoni
The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil; Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
Helder Tedeschi
The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil; Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
Fernando Cendes
The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil; Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
Fabio Rogerio
The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil; Department of Pathology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
Iscia Lopes-Cendes
Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), São Paulo, Brazil; The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil
Diogo F.T. Veiga
Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), São Paulo, Brazil; The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil; Corresponding author
Summary: Focal cortical dysplasia (FCD) is a neurodevelopmental condition characterized by malformations of the cerebral cortex that often cause drug-resistant epilepsy. In this study, we performed multi-omics single-nuclei profiling to map the chromatin accessibility and transcriptome landscapes of FCD type II, generating a comprehensive multimodal single-nuclei dataset comprising 61,525 cells from 11 clinical samples of lesions and controls. Our findings revealed profound chromatin, transcriptomic, and cellular alterations affecting neuronal and glial cells in FCD lesions, including the selective loss of upper-layer excitatory neurons, significant expansion of oligodendrocytes and immature astrocytic populations, and a distinct neuronal subpopulation harboring dysmorphic neurons. Furthermore, we uncovered activated microglia subsets, particularly in FCD IIb cases. This comprehensive study unveils neuronal and glial cell states driving FCD development and epileptogenicity, enhancing our understanding of FCD and offering directions for targeted therapy development.
