Flow blockage disrupts cilia-driven fluid transport in the epileptic brain
Flow blockage disrupts cilia-driven fluid transport in the epileptic brain
复制标题
DOI：
10.1007/s00401-022-02463-y
复制
发表时间：
2022-08-18
影响因子：
12.7
通讯作者：
Lo, Cecilia W.
中科院分区：
文献类型：
--
作者：
Faubel, Regina J.;Canellas, Veronica S. Santos;Lo, Cecilia W.
室管膜可移动的纤毛排列在脑室系统，形成一个流动通道和屏障的网络，使脑脊液(CSF)在表面流动。这种脑脊液转运系统在进化上是保守的，但其生理功能尚不清楚。在这里，我们通过研究CDKL5缺乏症(CDD)来研究它在癫痫中的潜在作用。CDKL5缺乏症是一种神经发育障碍，具有对癫痫药物无效的早发性癫痫，也是婴儿癫痫的最常见原因。CDKL5是一个高度保守的X连锁基因，提示其在调节绿藻衣藻纤毛长度和运动中的功能可能与CDD的病因学有关。对CDD患者和CDKL5基因敲除小鼠的呼吸道运动纤毛结构和功能的检查显示，CDD患者和CDKL5基因敲除小鼠均表现出纤毛延长和异常纤毛运动。CDKL5基因敲除小鼠的脑室纤毛也有类似的缺陷。标测室管膜纤毛在腹侧第三脑室(V3V)产生的血流，这是一个具有重要生理功能的大脑区域，显示了改变的血流模式。荧光染料示踪纤毛介导的v3v流入CDKL5基因敲除小鼠的v3v入口处出现流动障碍。对另一种癫痫相关激酶Yes1突变的小鼠的分析显示，纤毛运动和流动模式也存在同样的障碍。在Foxj1(+/-)和FOXJ1Cre(ERT)：CDKL5(y/fl)小鼠中也观察到了血流障碍，证实了心室纤毛在血流障碍中的作用。重要的是，表现出纤毛驱动血流改变的小鼠也显示出对麻醉诱导的癫痫样活动的敏感性增加。纤毛驱动的流动扰动来自纤毛节拍方向的改变，纤毛锚定根网的极性被破坏。综上所述，这些发现表明，纤毛运动障碍在CDD相关癫痫发作及以后的发作中具有重要作用，提示纤毛调节激酶可能是药物耐药癫痫的治疗靶点。
A carpet of ependymal motile cilia lines the brain ventricular system, forming a network of flow channels and barriers that pattern cerebrospinal fluid (CSF) flow at the surface. This CSF transport system is evolutionary conserved, but its physiological function remains unknown. Here we investigated its potential role in epilepsy with studies focused on CDKL5 deficiency disorder (CDD), a neurodevelopmental disorder with early-onset epilepsy refractory to seizure medications and the most common cause of infant epilepsy. CDKL5 is a highly conserved X-linked gene suggesting its function in regulating cilia length and motion in the green alga Chlamydomonas might have implication in the etiology of CDD. Examination of the structure and function of airway motile cilia revealed both the CDD patients and the Cdkl5 knockout mice exhibit cilia lengthening and abnormal cilia motion. Similar defects were observed for brain ventricular cilia in the Cdkl5 knockout mice. Mapping ependymal cilia generated flow in the ventral third ventricle (v3V), a brain region with important physiological functions showed altered patterning of flow. Tracing of cilia-mediated inflow into v3V with fluorescent dye revealed the appearance of a flow barrier at the inlet of v3V in Cdkl5 knockout mice. Analysis of mice with a mutation in another epilepsy-associated kinase, Yes1, showed the same disturbance of cilia motion and flow patterning. The flow barrier was also observed in the Foxj1(+/-) and FOXJ1Cre(ERT):Cdkl5(y/fl) mice, confirming the contribution of ventricular cilia to the flow disturbances. Importantly, mice exhibiting altered cilia-driven flow also showed increased susceptibility to anesthesia-induced seizure-like activity. The cilia-driven flow disturbance arises from altered cilia beating orientation with the disrupted polarity of the cilia anchoring rootlet meshwork. Together these findings indicate motile cilia disturbances have an essential role in CDD-associated seizures and beyond, suggesting cilia regulating kinases may be a therapeutic target for medication-resistant epilepsy.