Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts

Mohit Dubey, Eelke Brouwers, Eline M C Hamilton, Oliver Stiedl, Marianna Bugiani, Henner Koch, Maarten H P Kole, Ursula Boschert, Robert C Wykes, Huibert D Mansvelder, Marjo S van der Knaap, Rogier Min

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

OBJECTIVE: Loss of function of the astrocyte-specific protein MLC1 leads to the childhood-onset leukodystrophy "megalencephalic leukoencephalopathy with subcortical cysts" (MLC). Studies on isolated cells show a role for MLC1 in astrocyte volume regulation and suggest that disturbed brain ion and water homeostasis is central to the disease. Excitability of neuronal networks is particularly sensitive to ion and water homeostasis. In line with this, reports of seizures and epilepsy in MLC patients exist. However, systematic assessment and mechanistic understanding of seizures in MLC are lacking.

METHODS: We analyzed an MLC patient inventory to study occurrence of seizures in MLC. We used two distinct genetic mouse models of MLC to further study epileptiform activity and seizure threshold through wireless extracellular field potential recordings. Whole-cell patch-clamp recordings and K+ -sensitive electrode recordings in mouse brain slices were used to explore the underlying mechanisms of epilepsy in MLC.

RESULTS: An early onset of seizures is common in MLC. Similarly, in MLC mice, we uncovered spontaneous epileptiform brain activity and a lowered threshold for induced seizures. At the cellular level, we found that although passive and active properties of individual pyramidal neurons are unchanged, extracellular K+ dynamics and neuronal network activity are abnormal in MLC mice.

INTERPRETATION: Disturbed astrocyte regulation of ion and water homeostasis in MLC causes hyperexcitability of neuronal networks and seizures. These findings suggest a role for defective astrocyte volume regulation in epilepsy. Ann Neurol 2018;83:636-649.

Original languageEnglish
Pages (from-to)636-649
Number of pages14
JournalAnnals of Neurology
Volume83
Issue number3
DOIs
Publication statusPublished - Mar 2018

Cite this

Dubey, Mohit ; Brouwers, Eelke ; Hamilton, Eline M C ; Stiedl, Oliver ; Bugiani, Marianna ; Koch, Henner ; Kole, Maarten H P ; Boschert, Ursula ; Wykes, Robert C ; Mansvelder, Huibert D ; van der Knaap, Marjo S ; Min, Rogier. / Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts. In: Annals of Neurology. 2018 ; Vol. 83, No. 3. pp. 636-649.
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title = "Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts",
abstract = "OBJECTIVE: Loss of function of the astrocyte-specific protein MLC1 leads to the childhood-onset leukodystrophy {"}megalencephalic leukoencephalopathy with subcortical cysts{"} (MLC). Studies on isolated cells show a role for MLC1 in astrocyte volume regulation and suggest that disturbed brain ion and water homeostasis is central to the disease. Excitability of neuronal networks is particularly sensitive to ion and water homeostasis. In line with this, reports of seizures and epilepsy in MLC patients exist. However, systematic assessment and mechanistic understanding of seizures in MLC are lacking.METHODS: We analyzed an MLC patient inventory to study occurrence of seizures in MLC. We used two distinct genetic mouse models of MLC to further study epileptiform activity and seizure threshold through wireless extracellular field potential recordings. Whole-cell patch-clamp recordings and K+ -sensitive electrode recordings in mouse brain slices were used to explore the underlying mechanisms of epilepsy in MLC.RESULTS: An early onset of seizures is common in MLC. Similarly, in MLC mice, we uncovered spontaneous epileptiform brain activity and a lowered threshold for induced seizures. At the cellular level, we found that although passive and active properties of individual pyramidal neurons are unchanged, extracellular K+ dynamics and neuronal network activity are abnormal in MLC mice.INTERPRETATION: Disturbed astrocyte regulation of ion and water homeostasis in MLC causes hyperexcitability of neuronal networks and seizures. These findings suggest a role for defective astrocyte volume regulation in epilepsy. Ann Neurol 2018;83:636-649.",
author = "Mohit Dubey and Eelke Brouwers and Hamilton, {Eline M C} and Oliver Stiedl and Marianna Bugiani and Henner Koch and Kole, {Maarten H P} and Ursula Boschert and Wykes, {Robert C} and Mansvelder, {Huibert D} and {van der Knaap}, {Marjo S} and Rogier Min",
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language = "English",
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Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts. / Dubey, Mohit; Brouwers, Eelke; Hamilton, Eline M C; Stiedl, Oliver; Bugiani, Marianna; Koch, Henner; Kole, Maarten H P; Boschert, Ursula; Wykes, Robert C; Mansvelder, Huibert D; van der Knaap, Marjo S; Min, Rogier.

In: Annals of Neurology, Vol. 83, No. 3, 03.2018, p. 636-649.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts

AU - Dubey, Mohit

AU - Brouwers, Eelke

AU - Hamilton, Eline M C

AU - Stiedl, Oliver

AU - Bugiani, Marianna

AU - Koch, Henner

AU - Kole, Maarten H P

AU - Boschert, Ursula

AU - Wykes, Robert C

AU - Mansvelder, Huibert D

AU - van der Knaap, Marjo S

AU - Min, Rogier

N1 - © 2018 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

PY - 2018/3

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N2 - OBJECTIVE: Loss of function of the astrocyte-specific protein MLC1 leads to the childhood-onset leukodystrophy "megalencephalic leukoencephalopathy with subcortical cysts" (MLC). Studies on isolated cells show a role for MLC1 in astrocyte volume regulation and suggest that disturbed brain ion and water homeostasis is central to the disease. Excitability of neuronal networks is particularly sensitive to ion and water homeostasis. In line with this, reports of seizures and epilepsy in MLC patients exist. However, systematic assessment and mechanistic understanding of seizures in MLC are lacking.METHODS: We analyzed an MLC patient inventory to study occurrence of seizures in MLC. We used two distinct genetic mouse models of MLC to further study epileptiform activity and seizure threshold through wireless extracellular field potential recordings. Whole-cell patch-clamp recordings and K+ -sensitive electrode recordings in mouse brain slices were used to explore the underlying mechanisms of epilepsy in MLC.RESULTS: An early onset of seizures is common in MLC. Similarly, in MLC mice, we uncovered spontaneous epileptiform brain activity and a lowered threshold for induced seizures. At the cellular level, we found that although passive and active properties of individual pyramidal neurons are unchanged, extracellular K+ dynamics and neuronal network activity are abnormal in MLC mice.INTERPRETATION: Disturbed astrocyte regulation of ion and water homeostasis in MLC causes hyperexcitability of neuronal networks and seizures. These findings suggest a role for defective astrocyte volume regulation in epilepsy. Ann Neurol 2018;83:636-649.

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U2 - 10.1002/ana.25190

DO - 10.1002/ana.25190

M3 - Article

VL - 83

SP - 636

EP - 649

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

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