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

Author

Listed:
  • 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
    Harvard Medical School)

  • 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
    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)

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.

Suggested Citation

  • Ulrich Pfisterer & Viktor Petukhov & Samuel Demharter & Johanna Meichsner & Jonatan J. Thompson & Mykhailo Y. Batiuk & Andrea Asenjo-Martinez & Navneet A. Vasistha & Ashish Thakur & Jens Mikkelsen & I, 2020. "Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18752-7
    DOI: 10.1038/s41467-020-18752-7
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