Cargando…

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

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 transcriptomi...

Descripción completa

Detalles Bibliográficos
Autores principales: Pfisterer, Ulrich, Petukhov, Viktor, Demharter, Samuel, Meichsner, Johanna, Thompson, Jonatan J., Batiuk, Mykhailo Y., Martinez, Andrea Asenjo, Vasistha, Navneet A., Thakur, Ashish, Mikkelsen, Jens, Adorjan, Istvan, Pinborg, Lars H., Pers, Tune H., von Engelhardt, Jakob, Kharchenko, Peter V., Khodosevich, Konstantin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541486/
https://www.ncbi.nlm.nih.gov/pubmed/33028830
http://dx.doi.org/10.1038/s41467-020-18752-7
_version_ 1783591404678676480
author Pfisterer, Ulrich
Petukhov, Viktor
Demharter, Samuel
Meichsner, Johanna
Thompson, Jonatan J.
Batiuk, Mykhailo Y.
Martinez, Andrea Asenjo
Vasistha, Navneet A.
Thakur, Ashish
Mikkelsen, Jens
Adorjan, Istvan
Pinborg, Lars H.
Pers, Tune H.
von Engelhardt, Jakob
Kharchenko, Peter V.
Khodosevich, Konstantin
author_facet Pfisterer, Ulrich
Petukhov, Viktor
Demharter, Samuel
Meichsner, Johanna
Thompson, Jonatan J.
Batiuk, Mykhailo Y.
Martinez, Andrea Asenjo
Vasistha, Navneet A.
Thakur, Ashish
Mikkelsen, Jens
Adorjan, Istvan
Pinborg, Lars H.
Pers, Tune H.
von Engelhardt, Jakob
Kharchenko, Peter V.
Khodosevich, Konstantin
author_sort Pfisterer, Ulrich
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7541486
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-75414862020-10-19 Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis Pfisterer, Ulrich Petukhov, Viktor Demharter, Samuel Meichsner, Johanna Thompson, Jonatan J. Batiuk, Mykhailo Y. Martinez, Andrea Asenjo Vasistha, Navneet A. Thakur, Ashish Mikkelsen, Jens Adorjan, Istvan Pinborg, Lars H. Pers, Tune H. von Engelhardt, Jakob Kharchenko, Peter V. Khodosevich, Konstantin Nat Commun Article 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. Nature Publishing Group UK 2020-10-07 /pmc/articles/PMC7541486/ /pubmed/33028830 http://dx.doi.org/10.1038/s41467-020-18752-7 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Pfisterer, Ulrich
Petukhov, Viktor
Demharter, Samuel
Meichsner, Johanna
Thompson, Jonatan J.
Batiuk, Mykhailo Y.
Martinez, Andrea Asenjo
Vasistha, Navneet A.
Thakur, Ashish
Mikkelsen, Jens
Adorjan, Istvan
Pinborg, Lars H.
Pers, Tune H.
von Engelhardt, Jakob
Kharchenko, Peter V.
Khodosevich, Konstantin
Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis
title Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis
title_full Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis
title_fullStr Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis
title_full_unstemmed Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis
title_short Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis
title_sort identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541486/
https://www.ncbi.nlm.nih.gov/pubmed/33028830
http://dx.doi.org/10.1038/s41467-020-18752-7
work_keys_str_mv AT pfistererulrich identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT petukhovviktor identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT demhartersamuel identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT meichsnerjohanna identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT thompsonjonatanj identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT batiukmykhailoy identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT martinezandreaasenjo identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT vasisthanavneeta identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT thakurashish identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT mikkelsenjens identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT adorjanistvan identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT pinborglarsh identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT perstuneh identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT vonengelhardtjakob identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT kharchenkopeterv identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis
AT khodosevichkonstantin identificationofepilepsyassociatedneuronalsubtypesandgeneexpressionunderlyingepileptogenesis