Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2

Nico A. Jansen; Chelsey Linnenbank; Maarten Schenke; Rob A. Voskuyl; Maria S. Jorge; Georgii Krivoshein; Cor Breukel; Margot M. Linssen; Jill W.C. Claassens; Conny Brouwers; Sandra H. van Heiningen; Anders Heuck; Karin Lykke-Hartmann; Else A. Tolner; Arn M.J.M. van den Maagdenberg

doi:10.1016/j.nbd.2024.106714

Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2

Nico A. Jansen^*, Chelsey Linnenbank, Maarten Schenke, Rob A. Voskuyl, Maria S. Jorge, Georgii Krivoshein, Cor Breukel, Margot M. Linssen, Jill W.C. Claassens, Conny Brouwers, Sandra H. van Heiningen, Anders Heuck, Karin Lykke-Hartmann, Else A. Tolner, Arn M.J.M. van den Maagdenberg

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

The mechanisms of initiation of spreading depolarization (SD) are understudied due to a paucity of disease models with spontaneously occurring events. We here present a novel mouse model of familial hemiplegic migraine type 2 (FHM2), expressing the missense T345A-mutated α2 subunit of the Na⁺/K⁺ adenosine triphosphatase pump (Atp1a2^T345A). Homozygous Atp1a2^T345A mice showed regular spontaneous SDs that exhibit a diurnal rhythm and typically originate from the hippocampus. Heterozygous Atp1a2^T345A mice rarely exhibited spontaneous SDs and, for electrically induced SDs, only showed an increased propagation speed, whereas homozygotes showed both increased propagation and decreased threshold. Remarkably, despite hippocampal hyperexcitability, spontaneous SDs in Atp1a2^T345A mice were only rarely associated with epileptic behavior, and seizure expression during kindling was decreased. Spontaneous SDs could be prevented by modulation of persistent sodium currents. Hippocampal SDs occurred in the presence of an NMDA-receptor antagonist, but these events did not reach the cortex, suggesting that initiation and propagation of SD depend on different mechanisms in this model.

Original language	English
Article number	106714
Journal	Neurobiology of Disease
Volume	202
ISSN	0969-9961
DOIs	https://doi.org/10.1016/j.nbd.2024.106714
Publication status	Published - Nov 2024

Keywords

Familial hemiplegic migraine
Knock-in mouse model
Na/K-ATPase
NMDA receptor
Sodium current
Spreading depolarization
T345A

Access to Document

10.1016/j.nbd.2024.106714Licence: CC BY

Cite this

Jansen, N. A., Linnenbank, C., Schenke, M., Voskuyl, R. A., Jorge, M. S., Krivoshein, G., Breukel, C., Linssen, M. M., Claassens, J. W. C., Brouwers, C., van Heiningen, S. H., Heuck, A., Lykke-Hartmann, K., Tolner, E. A., & van den Maagdenberg, A. M. J. M. (2024). Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2. Neurobiology of Disease, 202, Article 106714. https://doi.org/10.1016/j.nbd.2024.106714

@article{978bf77b77ab4128844364d8dee279aa,

title = "Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2",

abstract = "The mechanisms of initiation of spreading depolarization (SD) are understudied due to a paucity of disease models with spontaneously occurring events. We here present a novel mouse model of familial hemiplegic migraine type 2 (FHM2), expressing the missense T345A-mutated α2 subunit of the Na+/K+ adenosine triphosphatase pump (Atp1a2T345A). Homozygous Atp1a2T345A mice showed regular spontaneous SDs that exhibit a diurnal rhythm and typically originate from the hippocampus. Heterozygous Atp1a2T345A mice rarely exhibited spontaneous SDs and, for electrically induced SDs, only showed an increased propagation speed, whereas homozygotes showed both increased propagation and decreased threshold. Remarkably, despite hippocampal hyperexcitability, spontaneous SDs in Atp1a2T345A mice were only rarely associated with epileptic behavior, and seizure expression during kindling was decreased. Spontaneous SDs could be prevented by modulation of persistent sodium currents. Hippocampal SDs occurred in the presence of an NMDA-receptor antagonist, but these events did not reach the cortex, suggesting that initiation and propagation of SD depend on different mechanisms in this model.",

keywords = "Familial hemiplegic migraine, Knock-in mouse model, Na/K-ATPase, NMDA receptor, Sodium current, Spreading depolarization, T345A",

author = "Jansen, {Nico A.} and Chelsey Linnenbank and Maarten Schenke and Voskuyl, {Rob A.} and Jorge, {Maria S.} and Georgii Krivoshein and Cor Breukel and Linssen, {Margot M.} and Claassens, {Jill W.C.} and Conny Brouwers and {van Heiningen}, {Sandra H.} and Anders Heuck and Karin Lykke-Hartmann and Tolner, {Else A.} and {van den Maagdenberg}, {Arn M.J.M.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = nov,

doi = "10.1016/j.nbd.2024.106714",

language = "English",

volume = "202",

journal = "Neurobiology of Disease",

issn = "0969-9961",

publisher = "Academic Press Inc.",

}

Jansen, NA, Linnenbank, C, Schenke, M, Voskuyl, RA, Jorge, MS, Krivoshein, G, Breukel, C, Linssen, MM, Claassens, JWC, Brouwers, C, van Heiningen, SH, Heuck, A , Lykke-Hartmann, K, Tolner, EA & van den Maagdenberg, AMJM 2024, 'Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2', Neurobiology of Disease, vol. 202, 106714. https://doi.org/10.1016/j.nbd.2024.106714

Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2. / Jansen, Nico A.; Linnenbank, Chelsey; Schenke, Maarten et al.
In: Neurobiology of Disease, Vol. 202, 106714, 11.2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2

AU - Jansen, Nico A.

AU - Linnenbank, Chelsey

AU - Schenke, Maarten

AU - Voskuyl, Rob A.

AU - Jorge, Maria S.

AU - Krivoshein, Georgii

AU - Breukel, Cor

AU - Linssen, Margot M.

AU - Claassens, Jill W.C.

AU - Brouwers, Conny

AU - van Heiningen, Sandra H.

AU - Heuck, Anders

AU - Lykke-Hartmann, Karin

AU - Tolner, Else A.

AU - van den Maagdenberg, Arn M.J.M.

PY - 2024/11

Y1 - 2024/11

N2 - The mechanisms of initiation of spreading depolarization (SD) are understudied due to a paucity of disease models with spontaneously occurring events. We here present a novel mouse model of familial hemiplegic migraine type 2 (FHM2), expressing the missense T345A-mutated α2 subunit of the Na+/K+ adenosine triphosphatase pump (Atp1a2T345A). Homozygous Atp1a2T345A mice showed regular spontaneous SDs that exhibit a diurnal rhythm and typically originate from the hippocampus. Heterozygous Atp1a2T345A mice rarely exhibited spontaneous SDs and, for electrically induced SDs, only showed an increased propagation speed, whereas homozygotes showed both increased propagation and decreased threshold. Remarkably, despite hippocampal hyperexcitability, spontaneous SDs in Atp1a2T345A mice were only rarely associated with epileptic behavior, and seizure expression during kindling was decreased. Spontaneous SDs could be prevented by modulation of persistent sodium currents. Hippocampal SDs occurred in the presence of an NMDA-receptor antagonist, but these events did not reach the cortex, suggesting that initiation and propagation of SD depend on different mechanisms in this model.

AB - The mechanisms of initiation of spreading depolarization (SD) are understudied due to a paucity of disease models with spontaneously occurring events. We here present a novel mouse model of familial hemiplegic migraine type 2 (FHM2), expressing the missense T345A-mutated α2 subunit of the Na+/K+ adenosine triphosphatase pump (Atp1a2T345A). Homozygous Atp1a2T345A mice showed regular spontaneous SDs that exhibit a diurnal rhythm and typically originate from the hippocampus. Heterozygous Atp1a2T345A mice rarely exhibited spontaneous SDs and, for electrically induced SDs, only showed an increased propagation speed, whereas homozygotes showed both increased propagation and decreased threshold. Remarkably, despite hippocampal hyperexcitability, spontaneous SDs in Atp1a2T345A mice were only rarely associated with epileptic behavior, and seizure expression during kindling was decreased. Spontaneous SDs could be prevented by modulation of persistent sodium currents. Hippocampal SDs occurred in the presence of an NMDA-receptor antagonist, but these events did not reach the cortex, suggesting that initiation and propagation of SD depend on different mechanisms in this model.

KW - Familial hemiplegic migraine

KW - Knock-in mouse model

KW - Na/K-ATPase

KW - NMDA receptor

KW - Sodium current

KW - Spreading depolarization

KW - T345A

UR - http://www.scopus.com/inward/record.url?scp=85208077615&partnerID=8YFLogxK

U2 - 10.1016/j.nbd.2024.106714

DO - 10.1016/j.nbd.2024.106714

M3 - Journal article

C2 - 39448040

AN - SCOPUS:85208077615

SN - 0969-9961

VL - 202

JO - Neurobiology of Disease

JF - Neurobiology of Disease

M1 - 106714

ER -

Spontaneous spreading depolarizations originate subcortically in a novel mouse model of familial hemiplegic migraine type 2

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this