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*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review


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
Issue number3
Early online date21 Feb 2018
Publication statusPublished - Mar 2018


This study was financially supported by E-Rare (11-330-1024), the Dutch Hersenstichting (2009(2)-14), an NWO Spinoza award (2008), and an Amsterdam Neuroscience proof-of-concept grant (2014).

FundersFunder number
Amsterdam Neuroscience
Anton Pieneman
Dr Tim Heistek
NWO Spinoza
Nederlandse Organisatie voor Wetenschappelijk Onderzoek


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