Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis

Ulrich Pfisterer, Viktor Petukhov, Samuel Demharter, Johanna Meichsner, Jonatan J. Thompson, Mykhailo Y. Batiuk, Andrea Asenjo-Martinez, Navneet A. Vasistha, Ashish Thakur, Jens Mikkelsen, Istvan Adorjan, Lars H. Pinborg, Tune H. Pers, Jakob Engelhardt, Peter V. Kharchenko and Konstantin Khodosevich ()
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Ulrich Pfisterer: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen
Viktor Petukhov: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen
Samuel Demharter: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen
Johanna Meichsner: University Medical Center of the Johannes Gutenberg University Mainz
Jonatan J. Thompson: Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Mykhailo Y. Batiuk: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen
Andrea Asenjo-Martinez: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen
Navneet A. Vasistha: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen
Ashish Thakur: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen
Jens Mikkelsen: Copenhagen University Hospital
Istvan Adorjan: Histology and Embryology, Semmelweis University
Lars H. Pinborg: Copenhagen University Hospital
Tune H. Pers: Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen
Jakob Engelhardt: University Medical Center of the Johannes Gutenberg University Mainz
Peter V. Kharchenko: Harvard Medical School
Konstantin Khodosevich: Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: Abstract Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy.

Date: 2020
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DOI: 10.1038/s41467-020-18752-7

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