Department of Child Neurology, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, The Netherlands.
Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, The Netherlands.
Ann Neurol. 2018 Mar;83(3):636-649. doi: 10.1002/ana.25190. Epub 2018 Mar 13.
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.
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.
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.
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.
星形胶质细胞特异性蛋白 MLC1 功能丧失会导致儿童发病的脑白质营养不良“巨脑性脑白质病伴皮质下囊肿”（MLC）。对分离细胞的研究表明，MLC1 在星形胶质细胞体积调节中起作用，并提示脑离子和水动态平衡紊乱是疾病的核心。神经元网络的兴奋性对离子和水动态平衡特别敏感。与此一致的是，存在 MLC 患者癫痫发作和癫痫的报道。然而，对 MLC 中癫痫发作的系统评估和机制理解仍然缺乏。
我们分析了 MLC 患者的病历，以研究 MLC 中癫痫发作的发生情况。我们使用两种不同的 MLC 基因小鼠模型，通过无线细胞外场电位记录进一步研究癫痫样活动和癫痫发作阈值。使用全细胞膜片钳记录和 K 敏感电极记录在小鼠脑切片中，探索 MLC 中癫痫的潜在机制。
在 MLC 中，癫痫发作的早期发作较为常见。同样，在 MLC 小鼠中，我们发现了自发性癫痫样脑活动和诱导性癫痫发作的阈值降低。在细胞水平上，我们发现尽管单个锥体神经元的被动和主动特性不变，但 MLC 小鼠的细胞外 K 动力学和神经元网络活动异常。
在 MLC 中，星形胶质细胞对离子和水动态平衡的调节障碍导致神经元网络的过度兴奋和癫痫发作。这些发现提示了星形胶质细胞体积调节缺陷在癫痫中的作用。
