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Updated: Sep 21, 2025
Lipidomics and Transcriptomics in Neurological Diseases
Published on: March 18, 2022
Transcriptomic profiling of nonneoplastic cortical tissues reveals epileptogenic mechanisms in dysembryoplastic
Krishan Kumar1, Aparna Banerjee Dixit1, Manjari Tripathi2
1Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.
Abstract:
Low-grade dysembryoplastic neuroepithelial tumors (DNTs) are a frequent cause of drug-refractory epilepsy. Molecular mechanisms underlying seizure generation in these tumors are poorly understood. This study was conducted to identify altered genes in nonneoplastic epileptogenic cortical tissues (ECTs) resected from DNT patients during electrocorticography (ECoG)-guided surgery. RNA sequencing (RNAseq) was used to determine the differentially expressed genes (DEGs) in these high-spiking ECTs compared to non-epileptic controls. A total of 477 DEGs (180 upregulated; 297 downregulated) were observed in the ECTs compared to non-epileptic controls. Gene ontology analysis revealed enrichment of genes belonging to the following Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways: (i) glutamatergic synapse; (ii) nitrogen metabolism; (iii) transcriptional misregulation in cancer; and (iv) protein digestion and absorption. The glutamatergic synapse pathway was enriched by DEGs such as GRM4, SLC1A6, GRIN2C, GRM2, GRM5, GRIN3A, and GRIN2B. Enhanced glutamatergic activity was observed in the pyramidal neurons of ECTs, which could be attributed to altered synaptic transmission in these tissues compared to non-epileptic controls. Besides glutamatergic synapse, altered expression of other genes such as GABRB1 (synapse formation), SLIT2 (axonal growth), and PROKR2 (neuron migration) could be linked to epileptogenesis in ECTs. Also, upregulation of GABRA6 gene in ECTs could underlie benzodiazepine resistance in these patients. Neural cell-type-specific gene set enrichment analysis (GSEA) revealed transcriptome of ECTs to be predominantly contributed by microglia and neurons. This study provides first comprehensive gene expression profiling of nonneoplastic ECTs of DNT patients and identifies genes/pathways potentially linked to epileptogenesis.
Insights
This study identified altered genes in brain tissue from patients with dysembryoplastic neuroepithelial tumors (DNTs), revealing key pathways like the glutamatergic synapse that may drive epilepsy. Findings offer insights into drug resistance and seizure generation mechanisms.
Area of Science:
- Neuroscience
- Genomics
- Molecular Biology
Background:
- Low-grade dysembryoplastic neuroepithelial tumors (DNTs) are a primary cause of drug-refractory epilepsy.
- The molecular underpinnings of seizure generation in DNTs remain largely unknown.
Purpose of the Study:
- To identify differentially expressed genes (DEGs) in nonneoplastic epileptogenic cortical tissues (ECTs) from DNT patients.
- To elucidate molecular pathways contributing to epileptogenesis in DNT-associated epilepsy.
Main Methods:
- RNA sequencing (RNAseq) was employed to compare gene expression in ECTs from DNT patients versus non-epileptic controls.
- Gene ontology and pathway analyses (KEGG) were performed on identified DEGs.
- Neural cell-type-specific gene set enrichment analysis (GSEA) was utilized.
Main Results:
- A total of 477 DEGs were identified, with 180 upregulated and 297 downregulated in ECTs.
- Enrichment analysis highlighted the glutamatergic synapse pathway, alongside nitrogen metabolism and cancer-related pathways.
- Upregulation of GRM4, SLC1A6, GRIN2C, and other genes involved in glutamatergic transmission was observed, suggesting enhanced neuronal activity.
- Altered expression of GABRB1, SLIT2, PROKR2, and GABRA6 suggests roles in synaptic formation, axonal growth, neuron migration, and potential benzodiazepine resistance.
Conclusions:
- This study presents the first comprehensive gene expression profile of nonneoplastic ECTs in DNT patients.
- Dysregulation of the glutamatergic synapse and other pathways are implicated in epileptogenesis and drug resistance.
- The findings provide a foundation for understanding DNT-associated epilepsy and developing targeted therapies.
