Brain cell atlas maps path to new epilepsy treatments
A groundbreaking single-cell sequencing study has produced the first comprehensive cellular atlas of focal cortical dysplasia (FCD), offering unprecedented insights into the molecular mechanisms underlying this severe form of drug-resistant epilepsy. The research, conducted by Brazilian scientists, maps both transcriptional and epigenetic changes at cellular resolution.
Dysmorphic neurons (left) and balloon-shaped cells (right) are associated with focal cortical dysplasia. © BRAINN/UNICAMP
Advancing understanding of cortical malformation
The study, published in iScience, analysed 61,525 single cells from 11 clinical samples, revealing distinct cellular subpopulations and pathological states within FCD lesions. This detailed molecular cartography identifies specific neuronal, microglial, and astrocytic populations that contribute to the condition’s pathogenesis.
Novel cellular signatures
Researchers identified a distinctive NEFM+ neuronal population containing dysmorphic neurons, which are implicated in the aberrant synaptic activity driving epileptic seizures. The team also discovered two previously unknown microglial subpopulations, designated as CD74+ and CD83+, associated with immune activation and neuroinflammation.
“Using an advanced genomic technique, we obtained a cellular and therefore extremely detailed view of this brain malformation,” explains computational biologist Diogo Veiga from the State University of Campinas. “We identified profound cellular changes in the cortex of these patients, including the loss of neurons in the upper layers, as well as immature astrocytes and populations of microglia expanded in the lesions and associated with inflammation.”
Therapeutic implications
The atlas reveals significant alterations in cortical architecture and cellular function, providing potential therapeutic targets for this challenging condition. FCD affects predominantly children and adolescents, accounting for up to 50% of paediatric epilepsy surgeries. Current treatment options are limited, with patients experiencing up to 50 seizures daily when medications fail.
Data sharing advancement
The research team has integrated their findings into the CellxGene database, part of the Human Cell Atlas Consortium, facilitating global collaborative efforts. “This type of data sharing is essential today to accelerate progress in medical research. We’re making available data generated with public money, returning society’s investment for the benefit of all,” notes researcher Iscia Lopes-Cendes.
Future directions
The research group is now extending their single-cell analysis approach to investigate infant brain development and other forms of dysplasia, seeking to identify potential mechanistic overlaps. This comparative analysis could reveal common pathways amenable to therapeutic intervention.
The study represents a significant advancement in understanding the cellular basis of FCD and exemplifies the power of single-cell sequencing techniques in elucidating complex neurological conditions. By providing a detailed cellular and molecular landscape of FCD, this research establishes a foundation for developing targeted treatments that could transform the management of drug-resistant epilepsy.
Reference:
Galvão, I. C., et al. (2024). Multimodal single-cell profiling reveals neuronal vulnerability and pathological cell states in focal cortical dysplasia. iScience. November 5, 2024. https://doi.org/10.1016/j.isci.2024.111337
