Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts.
Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts.
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DOI：
10.1002/ana.25190
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发表时间：
2018-03
影响因子：
11.2
通讯作者：
Min R
中科院分区：
文献类型：
--
作者：
Dubey M;Brouwers E;Hamilton EMC;Stiedl O;Bugiani M;Koch H;Kole MHP;Boschert U;Wykes RC;Mansvelder HD;van der Knaap MS;Min R
星形胶质细胞特异性蛋白MLC 1的功能丧失导致儿童期脑白质营养不良“巨脑白质脑病伴皮质下囊肿”（MLC）。对分离细胞的研究显示MLC 1在星形胶质细胞体积调节中的作用，并表明脑离子和水稳态紊乱是该疾病的核心。神经元网络的兴奋性对离子和水的稳态特别敏感。与此一致，MLC患者中存在癫痫发作和癫痫的报告。然而，缺乏系统的评估和机制的理解，在MLC的癫痫发作。我们分析了MLC患者库存，以研究MLC中癫痫发作的发生率。我们使用了两种不同的遗传小鼠模型的MLC进一步研究癫痫样活动和癫痫发作阈值，通过无线胞外场电位记录。采用全细胞膜片钳记录和小鼠脑切片中的K+敏感电极记录来探索MLC中癫痫的潜在机制。早期发作的癫痫发作是常见的MLC。同样，在MLC小鼠中，我们发现自发性癫痫样脑活动和诱导癫痫发作的阈值降低。在细胞水平上，我们发现，虽然被动和主动特性的个别锥体神经元是不变的，细胞外K+动力学和神经元网络的活动是异常的MLC小鼠。MLC中星形胶质细胞对离子和水稳态的调节紊乱导致神经元网络的过度兴奋和癫痫发作。这些研究结果表明，缺陷的星形胶质细胞体积调节癫痫的作用。神经学年鉴2018;83：636-649
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
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影响因子：
5.3
作者：
Djukic, Biljana;Casper, Kristen B.;McCarthy, Ken D.
通讯作者：
McCarthy, Ken D.
影响因子：
5.3
作者：
Bugiani M;Dubey M;Breur M;Postma NL;Dekker MP;Ter Braak T;Boschert U;Abbink TEM;Mansvelder HD;Min R;van Weering JRT;van der Knaap MS
通讯作者：
van der Knaap MS
影响因子：
16.6
作者：
Kaetzel, Dennis;Nicholson, Elizabeth;Schorge, Stephanie;Walker, Matthew C.;Kullmann, Dimitri M.
通讯作者：
Kullmann, Dimitri M.
影响因子：
9.8
作者：
Leegwater, PAJ;Yuan, BQ;van der Knaap, MS
通讯作者：
van der Knaap, MS
影响因子：
3
作者：
HORIKAWA, K;ARMSTRONG, WE
通讯作者：
ARMSTRONG, WE