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Research Articles, Cellular/Molecular

Calcium Channel Subunit α2δ4 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 and Susanne Schoch
Journal of Neuroscience 24 April 2019, 39 (17) 3175-3187; DOI: https://doi.org/10.1523/JNEUROSCI.1731-18.2019
Karen M.J. van Loo
1Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, 53105 Bonn, Germany,
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Christine K. Rummel
1Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, 53105 Bonn, Germany,
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Julika Pitsch
1Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, 53105 Bonn, Germany,
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Johannes Alexander Müller
1Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, 53105 Bonn, Germany,
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Arthur F. Bikbaev
2RG Molecular Physiology, Leibniz Institute for Neurobiology, Center for Behavioral Brain Science, Otto-von-Guericke-University of Magdeburg, 39118 Magdeburg, Germany,
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Erick Martinez-Chavez
3Institute of Reconstructive Neurobiology, University of Bonn Medical Center, 53105 Bonn, Germany, and
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Sandra Blaess
3Institute of Reconstructive Neurobiology, University of Bonn Medical Center, 53105 Bonn, Germany, and
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Dirk Dietrich
4Department of Neurosurgery, University of Bonn Medical Center, 53105 Bonn, Germany
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Martin Heine
2RG Molecular Physiology, Leibniz Institute for Neurobiology, Center for Behavioral Brain Science, Otto-von-Guericke-University of Magdeburg, 39118 Magdeburg, Germany,
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Albert J. Becker
1Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, 53105 Bonn, Germany,
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Susanne Schoch
1Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, 53105 Bonn, Germany,
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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. We found Egr1 to drive the expression of the VDCC subunit α2δ4, which was augmented early and persistently after pilocarpine-induced SE. Furthermore, we show that increasing levels of α2δ4 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 and α2δ4 in human hippocampal biopsies obtained from epilepsy surgery. In conclusion, Egr1 controls the abundance of the VDCC subunits CaV3.2 and α2δ4, which act synergistically in epileptogenesis, and thereby contributes to a seizure-induced “transcriptional Ca2+ channelopathy.”

SIGNIFICANCE STATEMENT The onset of focal recurrent seizures often occurs after an epileptogenic process induced by transient insults to the brain. Recently, transcriptional control mechanisms for individual genes involved in converting neurons hyperexcitable have been identified, including early growth response 1 (Egr1), which activates transcription of the T-type Ca2+ channel subunit CaV3.2. Here, we find Egr1 to regulate also the expression of the voltage-dependent Ca2+ channel subunit α2δ4, which was augmented after pilocarpine- and kainic acid-induced status epilepticus. In addition, we observed that α2δ4 affected spontaneous network activity and the susceptibility for seizure induction. Furthermore, we detected corresponding dynamics in human biopsies from epilepsy patients. In conclusion, Egr1 orchestrates a seizure-induced “transcriptional Ca2+ channelopathy” consisting of CaV3.2 and α2δ4, which act synergistically in epileptogenesis.

  • Cacna2d4
  • CaV3.2
  • early growth response 1
  • epileptogenesis
  • pilocarpine and kainic acid-induced status epilepticus
  • transcriptional Ca2+ channelopathy
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The Journal of Neuroscience: 39 (17)
Journal of Neuroscience
Vol. 39, Issue 17
24 Apr 2019
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Calcium Channel Subunit α2δ4 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
Journal of Neuroscience 24 April 2019, 39 (17) 3175-3187; DOI: 10.1523/JNEUROSCI.1731-18.2019

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Calcium Channel Subunit α2δ4 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
Journal of Neuroscience 24 April 2019, 39 (17) 3175-3187; DOI: 10.1523/JNEUROSCI.1731-18.2019
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Keywords

  • Cacna2d4
  • Cav3.2
  • early growth response 1
  • epileptogenesis
  • pilocarpine and kainic acid-induced status epilepticus
  • transcriptional Ca2+ channelopathy

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