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- Title
Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts.
- Authors
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
- Abstract
<bold>Objective: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Interpretation: </bold>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.
- Subjects
POTASSIUM in the body; LEUKODYSTROPHY; PROGRESSIVE multifocal leukoencephalopathy; CYSTS (Pathology); LABORATORY mice; CELL metabolism; POTASSIUM metabolism; BRAIN metabolism; ANIMAL experimentation; COMPARATIVE studies; SEIZURES (Medicine); DEMYELINATION; LYSOSOMAL storage diseases; RESEARCH methodology; MEDICAL cooperation; MEMBRANE proteins; MICE; GENETIC mutation; RESEARCH; SPASMS; EVALUATION research; HEREDITARY central nervous system demyelinating diseases
- Publication
Annals of Neurology, 2018, Vol 83, Issue 3, p636
- ISSN
0364-5134
- Publication type
journal article
- DOI
10.1002/ana.25190