TY - JOUR
T1 - Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis
T2 - [incl. Author Correction]
AU - Pfisterer, Ulrich
AU - Petukhov, Viktor
AU - Demharter, Samuel
AU - Meichsner, Johanna
AU - Thompson, Jonatan J.
AU - Batiuk, Mykhailo Y.
AU - Martinez, Andrea Asenjo
AU - Vasistha, Navneet A.
AU - Thakur, Ashish
AU - Mikkelsen, Jens
AU - Adorjan, Istvan
AU - Pinborg, Lars H.
AU - Pers, Tune H.
AU - von Engelhardt, Jakob
AU - Kharchenko, Peter V.
AU - Khodosevich, Konstantin
N1 - Author Correction: Identification of epilepsy-associated neuronal subtypes and gene expression underlying epileptogenesis (Nature Communications, (2020), 11, 1, (5038)
DOI: 10.1038/s41467-020-19869-5
https://www.nature.com/articles/s41467-020-19869-5
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - RNA-SEQ
KW - MOUSE MODEL
KW - PARVALBUMIN
KW - NEOCORTEX
KW - BRAIN
KW - TRANSCRIPTOME
KW - ABNORMALITIES
KW - INTERNEURONS
KW - EXCITABILITY
KW - PERAMPANEL
UR - https://doi.org/10.1038/s41467-020-19869-5
U2 - 10.1038/s41467-020-18752-7
DO - 10.1038/s41467-020-18752-7
M3 - Journal article
C2 - 33028830
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5038
ER -