CaV3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons

Stuart M. Cain, John R. Tyson, Hyun Beom Choi, Rebecca Ko, Paulo J.C. Lin, Jeffrey M. Ledue, Kim L. Powell, Louis Philippe Bernier, Ravi L. Rungta, Yi Yang, Pieter R. Cullis, Terence J. O'Brien, Brian A. Macvicar, Terrance P. Snutch

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

Objective: Genetic alterations have been identified in the CACNA1H gene, encoding the CaV3.2 T-type calcium channel in patients with absence epilepsy, yet the precise mechanisms relating to seizure propagation and spike-wave-discharge (SWD) pacemaking remain unknown. Neurons of the thalamic reticular nucleus (TRN) express high levels of CaV3.2 calcium channels, and we investigated whether a gain-of-function mutation in the Cacna1h gene in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) contributes to seizure propagation and pacemaking in the TRN. Methods: Pathophysiological contributions of CaV3.2 calcium channels to burst firing and absence seizures were assessed in vitro using acute brain slice electrophysiology and quantitative real-time polymerase chain reaction (PCR) and in vivo using free-moving electrocorticography recordings. Results: TRN neurons from GAERS display sustained oscillatory burst-firing that is both age- and frequency-dependent, occurring only in the frequencies overlapping with GAERS SWDs and correlating with the expression of a CaV3.2 mutation-sensitive splice variant. In vivo knock-down of CaV3.2 using direct thalamic injection of lipid nanoparticles containing CaV3.2 dicer small interfering (Dsi) RNA normalized TRN burst-firing, and in free-moving GAERS significantly shortened seizures. Significance: This supports a role for TRN CaV3.2 T-type channels in propagating thalamocortical network seizures and setting the pacemaking frequency of SWDs.

Original languageEnglish
Pages (from-to)778-791
Number of pages14
JournalEpilepsia
Volume59
Issue number4
DOIs
Publication statusPublished - Apr 2018

Keywords

  • Absence epilepsy
  • Low threshold spike
  • T-type calcium channel
  • Thalamocortical

Cite this

Cain, S. M., Tyson, J. R., Choi, H. B., Ko, R., Lin, P. J. C., Ledue, J. M., ... Snutch, T. P. (2018). CaV3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons. Epilepsia, 59(4), 778-791. https://doi.org/10.1111/epi.14018
Cain, Stuart M. ; Tyson, John R. ; Choi, Hyun Beom ; Ko, Rebecca ; Lin, Paulo J.C. ; Ledue, Jeffrey M. ; Powell, Kim L. ; Bernier, Louis Philippe ; Rungta, Ravi L. ; Yang, Yi ; Cullis, Pieter R. ; O'Brien, Terence J. ; Macvicar, Brian A. ; Snutch, Terrance P. / CaV3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons. In: Epilepsia. 2018 ; Vol. 59, No. 4. pp. 778-791.
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title = "CaV3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons",
abstract = "Objective: Genetic alterations have been identified in the CACNA1H gene, encoding the CaV3.2 T-type calcium channel in patients with absence epilepsy, yet the precise mechanisms relating to seizure propagation and spike-wave-discharge (SWD) pacemaking remain unknown. Neurons of the thalamic reticular nucleus (TRN) express high levels of CaV3.2 calcium channels, and we investigated whether a gain-of-function mutation in the Cacna1h gene in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) contributes to seizure propagation and pacemaking in the TRN. Methods: Pathophysiological contributions of CaV3.2 calcium channels to burst firing and absence seizures were assessed in vitro using acute brain slice electrophysiology and quantitative real-time polymerase chain reaction (PCR) and in vivo using free-moving electrocorticography recordings. Results: TRN neurons from GAERS display sustained oscillatory burst-firing that is both age- and frequency-dependent, occurring only in the frequencies overlapping with GAERS SWDs and correlating with the expression of a CaV3.2 mutation-sensitive splice variant. In vivo knock-down of CaV3.2 using direct thalamic injection of lipid nanoparticles containing CaV3.2 dicer small interfering (Dsi) RNA normalized TRN burst-firing, and in free-moving GAERS significantly shortened seizures. Significance: This supports a role for TRN CaV3.2 T-type channels in propagating thalamocortical network seizures and setting the pacemaking frequency of SWDs.",
keywords = "Absence epilepsy, Low threshold spike, T-type calcium channel, Thalamocortical",
author = "Cain, {Stuart M.} and Tyson, {John R.} and Choi, {Hyun Beom} and Rebecca Ko and Lin, {Paulo J.C.} and Ledue, {Jeffrey M.} and Powell, {Kim L.} and Bernier, {Louis Philippe} and Rungta, {Ravi L.} and Yi Yang and Cullis, {Pieter R.} and O'Brien, {Terence J.} and Macvicar, {Brian A.} and Snutch, {Terrance P.}",
year = "2018",
month = "4",
doi = "10.1111/epi.14018",
language = "English",
volume = "59",
pages = "778--791",
journal = "Epilepsia",
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Cain, SM, Tyson, JR, Choi, HB, Ko, R, Lin, PJC, Ledue, JM, Powell, KL, Bernier, LP, Rungta, RL, Yang, Y, Cullis, PR, O'Brien, TJ, Macvicar, BA & Snutch, TP 2018, 'CaV3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons', Epilepsia, vol. 59, no. 4, pp. 778-791. https://doi.org/10.1111/epi.14018

CaV3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons. / Cain, Stuart M.; Tyson, John R.; Choi, Hyun Beom; Ko, Rebecca; Lin, Paulo J.C.; Ledue, Jeffrey M.; Powell, Kim L.; Bernier, Louis Philippe; Rungta, Ravi L.; Yang, Yi; Cullis, Pieter R.; O'Brien, Terence J.; Macvicar, Brian A.; Snutch, Terrance P.

In: Epilepsia, Vol. 59, No. 4, 04.2018, p. 778-791.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - CaV3.2 drives sustained burst-firing, which is critical for absence seizure propagation in reticular thalamic neurons

AU - Cain, Stuart M.

AU - Tyson, John R.

AU - Choi, Hyun Beom

AU - Ko, Rebecca

AU - Lin, Paulo J.C.

AU - Ledue, Jeffrey M.

AU - Powell, Kim L.

AU - Bernier, Louis Philippe

AU - Rungta, Ravi L.

AU - Yang, Yi

AU - Cullis, Pieter R.

AU - O'Brien, Terence J.

AU - Macvicar, Brian A.

AU - Snutch, Terrance P.

PY - 2018/4

Y1 - 2018/4

N2 - Objective: Genetic alterations have been identified in the CACNA1H gene, encoding the CaV3.2 T-type calcium channel in patients with absence epilepsy, yet the precise mechanisms relating to seizure propagation and spike-wave-discharge (SWD) pacemaking remain unknown. Neurons of the thalamic reticular nucleus (TRN) express high levels of CaV3.2 calcium channels, and we investigated whether a gain-of-function mutation in the Cacna1h gene in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) contributes to seizure propagation and pacemaking in the TRN. Methods: Pathophysiological contributions of CaV3.2 calcium channels to burst firing and absence seizures were assessed in vitro using acute brain slice electrophysiology and quantitative real-time polymerase chain reaction (PCR) and in vivo using free-moving electrocorticography recordings. Results: TRN neurons from GAERS display sustained oscillatory burst-firing that is both age- and frequency-dependent, occurring only in the frequencies overlapping with GAERS SWDs and correlating with the expression of a CaV3.2 mutation-sensitive splice variant. In vivo knock-down of CaV3.2 using direct thalamic injection of lipid nanoparticles containing CaV3.2 dicer small interfering (Dsi) RNA normalized TRN burst-firing, and in free-moving GAERS significantly shortened seizures. Significance: This supports a role for TRN CaV3.2 T-type channels in propagating thalamocortical network seizures and setting the pacemaking frequency of SWDs.

AB - Objective: Genetic alterations have been identified in the CACNA1H gene, encoding the CaV3.2 T-type calcium channel in patients with absence epilepsy, yet the precise mechanisms relating to seizure propagation and spike-wave-discharge (SWD) pacemaking remain unknown. Neurons of the thalamic reticular nucleus (TRN) express high levels of CaV3.2 calcium channels, and we investigated whether a gain-of-function mutation in the Cacna1h gene in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) contributes to seizure propagation and pacemaking in the TRN. Methods: Pathophysiological contributions of CaV3.2 calcium channels to burst firing and absence seizures were assessed in vitro using acute brain slice electrophysiology and quantitative real-time polymerase chain reaction (PCR) and in vivo using free-moving electrocorticography recordings. Results: TRN neurons from GAERS display sustained oscillatory burst-firing that is both age- and frequency-dependent, occurring only in the frequencies overlapping with GAERS SWDs and correlating with the expression of a CaV3.2 mutation-sensitive splice variant. In vivo knock-down of CaV3.2 using direct thalamic injection of lipid nanoparticles containing CaV3.2 dicer small interfering (Dsi) RNA normalized TRN burst-firing, and in free-moving GAERS significantly shortened seizures. Significance: This supports a role for TRN CaV3.2 T-type channels in propagating thalamocortical network seizures and setting the pacemaking frequency of SWDs.

KW - Absence epilepsy

KW - Low threshold spike

KW - T-type calcium channel

KW - Thalamocortical

UR - http://www.scopus.com/inward/record.url?scp=85042233951&partnerID=8YFLogxK

U2 - 10.1111/epi.14018

DO - 10.1111/epi.14018

M3 - Article

VL - 59

SP - 778

EP - 791

JO - Epilepsia

JF - Epilepsia

SN - 0013-9580

IS - 4

ER -