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Single Cell Transcriptomics of Refractory Epilepsy (RE) patients in Colombia.

ABSTRACT: The human neocortex is composed of dozens to hundreds of distinct cell types, whose gene expression patterns maintain the balanced electric signaling during all the life. Although the brain has shown a high adaptive capacity to tolerate disruptions, some alterations in these genetic programs can contribute to the pathogenesis of various neurological disorders, including epilepsy, autism spectrum disorder, Alzheimer’s disease, and Parkinson’s disease. Genetic factors are especially implicated in a specific form known as refractory or drug-resistant epilepsy (DRE), which is diagnosed when two or more antiepileptic treatment regimens fail to control seizures. In this study, we investigated the cellular and molecular landscape of DRE using brain tissue from five pediatric Colombian patients. Six samples collected during surgical resection were analyzed using single-cell RNA sequencing (scRNA-seq) and long-read genome sequencing (PacBio HiFi). We identified differentially expressed genes (DEGs) across distinct cell types, integrating transcriptomic data with single nucleotide polymorphisms (SNPs), insertions, deletions, and structural variants. Functional enrichment analysis revealed glial-driven dysregulation of synaptic signaling, impaired glial–neuronal communication, and altered expression of transporters and calcium signaling genes. Notably, aberrant activation of taste receptors in neurons was associated with neuroinflammatory processes. These findings suggest that DRE arises from complex, cell-type-specific disruptions that compromise network stability and seizure control.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302285 | GEO | 2025/08/04

REPOSITORIES: GEO

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Project description:Neither the molecular basis of the pathologic tendency of neuronal circuits to generate spontaneous seizures (epileptogenicity) nor anti-epileptogenic mechanisms that maintain a seizure-free state are well understood. Here, we performed transcriptomic analysis in the intrahippocampal kainate model of temporal lobe epilepsy in rats using both Agilent and Codelink microarray platforms to characterize the epileptic processes. The experimental design allowed subtraction of the confounding effects of the lesion, identification of expression changes associated with epileptogenicity, and genes upregulated by seizures with potential homeostatic anti-epileptogenic effects. Using differential expression analysis, we identified several hundred expression changes in chronic epilepsy, including candidate genes associated with epileptogenicity such as Bdnf and Kcnj13. To analyze these data from a systems perspective, we applied weighted gene co-expression network analysis (WGCNA) to identify groups of co-expressed genes (modules) and their central (hub) genes. One such module contained genes upregulated in the epileptogenic region, including multiple epileptogenicity candidate genes, and was found to be involved the protection of glial cells against oxidative stress, implicating glial oxidative stress in epileptogenicity. Another distinct module corresponded to the effects of chronic seizures and represented changes in neuronal synaptic vesicle trafficking. We found that the network structure and connectivity of one hub gene, Sv2a, showed significant changes between normal and epileptogenic tissue, becoming more highly connected in epileptic brain. Since Sv2a is a target of the antiepileptic levetiracetam, this module may be important in controlling seizure activity. Bioinformatic analysis of this module also revealed a potential mechanism for the observed transcriptional changes via generation of longer alternatively polyadenlyated transcripts through the upregulation of the RNA binding protein HuD. In summary, combining conventional statistical methods and network analysis allowed us to interpret the differentially regulated genes from a systems perspective, yielding new insight into several biological pathways underlying homeostatic anti-epileptogenic effects and epileptogenicity. Four condition experiment with five samples per condition. The samples include right dentate gyrus from animals with seizures, left dentate gyrus from animals with seizures, right dentate gyrus from animals without seizures, and left dentate gyrus from animals without seizures. A dye swap was included.

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Single Cell Transcriptomics of Refractory Epilepsy (RE) patients in Colombia.

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