Calcium channel subunit α2σ4 is regulated by early growth response 1 and facilitates epileptogenesis

Karen M. J. van Loo, Christine K. Rummel, Julika Pitsch, Johannes Alexander Müller, Arthur F. Bikbaev, Erick Martinez-Chavez, Sandra Blaess, Dirk Dietrich, Martin Heine, Albert J. Becker, Susanne Schoch

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Transient brain insults, including status epilepticus (SE), can trigger a period of epileptogenesis during which functional and structural reorganization of neuronal networks occurs resulting in the onset of focal epileptic seizures. In recent years, mechanisms that regulate the dynamic transcription of individual genes during epileptogenesis and thereby contribute to the development of a hyperexcitable neuronal network have been elucidated. Our own results have shown early growth response 1 (Egr1) to transiently increase expression of the T-type voltage-dependent Ca2+ channel (VDCC) subunit CaV3.2, a key proepileptogenic protein. However, epileptogenesis involves complex and dynamic transcriptomic alterations; and so far, our understanding of the transcriptional control mechanism of gene regulatory networks that act in the same processes is limited. Here, we have analyzed whether Egr1 acts as a key transcriptional regulator for genes contributing to the development of hyperexcitability during epileptogenesis.Wefound Egr1 to drive the expression of theVDCC subunitα2σ4, which was augmented early and persistently after pilocarpine-induced SE. Furthermore, we show that increasing levels of α2σ4 in the CA1 region of the hippocampus elevate seizure susceptibility of mice by slightly decreasing local network activity. Interestingly, we also detected increased expression levels of Egr1 andα2σ4 in human hippocampal biopsies obtained from epilepsy surgery. In conclusion, Egr1 controls the abundance of theVDCCsubunits CaV3.2 andα2σ4, which act synergistically in epileptogenesis, and thereby contributes to a seizure-induced “transcriptional Ca2+ channelopathy".
Original languageEnglish
Pages (from-to)3175-3187
JournalJournal of Neuroscience
Volume39
Issue number17
DOIs
Publication statusPublished - 2019

Cite this

van Loo, K. M. J., Rummel, C. K., Pitsch, J., Müller, J. A., Bikbaev, A. F., Martinez-Chavez, E., ... Schoch, S. (2019). Calcium channel subunit α2σ4 is regulated by early growth response 1 and facilitates epileptogenesis. Journal of Neuroscience, 39(17), 3175-3187. https://doi.org/10.1523/JNEUROSCI.1731-18.2019
van Loo, Karen M. J. ; Rummel, Christine K. ; Pitsch, Julika ; Müller, Johannes Alexander ; Bikbaev, Arthur F. ; Martinez-Chavez, Erick ; Blaess, Sandra ; Dietrich, Dirk ; Heine, Martin ; Becker, Albert J. ; Schoch, Susanne. / Calcium channel subunit α2σ4 is regulated by early growth response 1 and facilitates epileptogenesis. In: Journal of Neuroscience. 2019 ; Vol. 39, No. 17. pp. 3175-3187.
@article{7ef16b02450c4133af574562db361765,
title = "Calcium channel subunit α2σ4 is regulated by early growth response 1 and facilitates epileptogenesis",
abstract = "Transient brain insults, including status epilepticus (SE), can trigger a period of epileptogenesis during which functional and structural reorganization of neuronal networks occurs resulting in the onset of focal epileptic seizures. In recent years, mechanisms that regulate the dynamic transcription of individual genes during epileptogenesis and thereby contribute to the development of a hyperexcitable neuronal network have been elucidated. Our own results have shown early growth response 1 (Egr1) to transiently increase expression of the T-type voltage-dependent Ca2+ channel (VDCC) subunit CaV3.2, a key proepileptogenic protein. However, epileptogenesis involves complex and dynamic transcriptomic alterations; and so far, our understanding of the transcriptional control mechanism of gene regulatory networks that act in the same processes is limited. Here, we have analyzed whether Egr1 acts as a key transcriptional regulator for genes contributing to the development of hyperexcitability during epileptogenesis.Wefound Egr1 to drive the expression of theVDCC subunitα2σ4, which was augmented early and persistently after pilocarpine-induced SE. Furthermore, we show that increasing levels of α2σ4 in the CA1 region of the hippocampus elevate seizure susceptibility of mice by slightly decreasing local network activity. Interestingly, we also detected increased expression levels of Egr1 andα2σ4 in human hippocampal biopsies obtained from epilepsy surgery. In conclusion, Egr1 controls the abundance of theVDCCsubunits CaV3.2 andα2σ4, which act synergistically in epileptogenesis, and thereby contributes to a seizure-induced “transcriptional Ca2+ channelopathy{"}.",
author = "{van Loo}, {Karen M. J.} and Rummel, {Christine K.} and Julika Pitsch and M{\"u}ller, {Johannes Alexander} and Bikbaev, {Arthur F.} and Erick Martinez-Chavez and Sandra Blaess and Dirk Dietrich and Martin Heine and Becker, {Albert J.} and Susanne Schoch",
year = "2019",
doi = "10.1523/JNEUROSCI.1731-18.2019",
language = "English",
volume = "39",
pages = "3175--3187",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "17",

}

van Loo, KMJ, Rummel, CK, Pitsch, J, Müller, JA, Bikbaev, AF, Martinez-Chavez, E, Blaess, S, Dietrich, D, Heine, M, Becker, AJ & Schoch, S 2019, 'Calcium channel subunit α2σ4 is regulated by early growth response 1 and facilitates epileptogenesis' Journal of Neuroscience, vol. 39, no. 17, pp. 3175-3187. https://doi.org/10.1523/JNEUROSCI.1731-18.2019

Calcium channel subunit α2σ4 is regulated by early growth response 1 and facilitates epileptogenesis. / van Loo, Karen M. J.; Rummel, Christine K.; Pitsch, Julika; Müller, Johannes Alexander; Bikbaev, Arthur F.; Martinez-Chavez, Erick; Blaess, Sandra; Dietrich, Dirk; Heine, Martin; Becker, Albert J.; Schoch, Susanne.

In: Journal of Neuroscience, Vol. 39, No. 17, 2019, p. 3175-3187.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Calcium channel subunit α2σ4 is regulated by early growth response 1 and facilitates epileptogenesis

AU - van Loo, Karen M. J.

AU - Rummel, Christine K.

AU - Pitsch, Julika

AU - Müller, Johannes Alexander

AU - Bikbaev, Arthur F.

AU - Martinez-Chavez, Erick

AU - Blaess, Sandra

AU - Dietrich, Dirk

AU - Heine, Martin

AU - Becker, Albert J.

AU - Schoch, Susanne

PY - 2019

Y1 - 2019

N2 - Transient brain insults, including status epilepticus (SE), can trigger a period of epileptogenesis during which functional and structural reorganization of neuronal networks occurs resulting in the onset of focal epileptic seizures. In recent years, mechanisms that regulate the dynamic transcription of individual genes during epileptogenesis and thereby contribute to the development of a hyperexcitable neuronal network have been elucidated. Our own results have shown early growth response 1 (Egr1) to transiently increase expression of the T-type voltage-dependent Ca2+ channel (VDCC) subunit CaV3.2, a key proepileptogenic protein. However, epileptogenesis involves complex and dynamic transcriptomic alterations; and so far, our understanding of the transcriptional control mechanism of gene regulatory networks that act in the same processes is limited. Here, we have analyzed whether Egr1 acts as a key transcriptional regulator for genes contributing to the development of hyperexcitability during epileptogenesis.Wefound Egr1 to drive the expression of theVDCC subunitα2σ4, which was augmented early and persistently after pilocarpine-induced SE. Furthermore, we show that increasing levels of α2σ4 in the CA1 region of the hippocampus elevate seizure susceptibility of mice by slightly decreasing local network activity. Interestingly, we also detected increased expression levels of Egr1 andα2σ4 in human hippocampal biopsies obtained from epilepsy surgery. In conclusion, Egr1 controls the abundance of theVDCCsubunits CaV3.2 andα2σ4, which act synergistically in epileptogenesis, and thereby contributes to a seizure-induced “transcriptional Ca2+ channelopathy".

AB - Transient brain insults, including status epilepticus (SE), can trigger a period of epileptogenesis during which functional and structural reorganization of neuronal networks occurs resulting in the onset of focal epileptic seizures. In recent years, mechanisms that regulate the dynamic transcription of individual genes during epileptogenesis and thereby contribute to the development of a hyperexcitable neuronal network have been elucidated. Our own results have shown early growth response 1 (Egr1) to transiently increase expression of the T-type voltage-dependent Ca2+ channel (VDCC) subunit CaV3.2, a key proepileptogenic protein. However, epileptogenesis involves complex and dynamic transcriptomic alterations; and so far, our understanding of the transcriptional control mechanism of gene regulatory networks that act in the same processes is limited. Here, we have analyzed whether Egr1 acts as a key transcriptional regulator for genes contributing to the development of hyperexcitability during epileptogenesis.Wefound Egr1 to drive the expression of theVDCC subunitα2σ4, which was augmented early and persistently after pilocarpine-induced SE. Furthermore, we show that increasing levels of α2σ4 in the CA1 region of the hippocampus elevate seizure susceptibility of mice by slightly decreasing local network activity. Interestingly, we also detected increased expression levels of Egr1 andα2σ4 in human hippocampal biopsies obtained from epilepsy surgery. In conclusion, Egr1 controls the abundance of theVDCCsubunits CaV3.2 andα2σ4, which act synergistically in epileptogenesis, and thereby contributes to a seizure-induced “transcriptional Ca2+ channelopathy".

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85065336425&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/30792272

U2 - 10.1523/JNEUROSCI.1731-18.2019

DO - 10.1523/JNEUROSCI.1731-18.2019

M3 - Article

VL - 39

SP - 3175

EP - 3187

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 17

ER -