Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA.
Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China.
Fluids Barriers CNS. 2022 Mar 5;19(1):20. doi: 10.1186/s12987-022-00319-x.
Hydrocephalus (increased ventricular size due to CSF accumulation) is a common finding in human ciliopathies and in mouse models with genetic depletion of the multiciliated cell (MCC) cilia machinery. However, the contribution of MCC to CSF dynamics and, the mechanism by which impaired MCC function leads to hydrocephalus remains poorly understood. The aim of our study was to examine if defects in MCC ciliogenesis and cilia-generated CSF flow impact central nervous system (CNS) fluid homeostasis including glymphatic transport and solute waste drainage.
We used two distinct mouse models of MCC ciliopathy: MCC-specific CEP164 conditional knockout mice (FOXJ1-Cre;CEP164 (N = 10), 3-month-old) and p73 knock-out (p73 (N = 8), 5-month-old) mice. Age-matched, wild-type littermates for each of the mutants served as controls. Glymphatic transport and solute drainage was quantified using in vivo T1 mapping by magnetic resonance imaging (MRI) after CSF infusion of gadoteric acid. Brain morphometry and aquaporin 4 expression (AQP4) was also assessed. Intracranial pressure (ICP) was measured in separate cohorts.
In both of the two models of MCC ciliopathy we found the ventriculomegaly to be associated with normal ICP. We showed that FOXJ1-Cre;CEP164 mice with hydrocephalus still demonstrated sustained glymphatic transport and normal AQP4 expression along capillaries. In p73 mice glymphatic transport was even increased, and this was paralleled by an increase in AQP4 polarization around capillaries. Further, solute drainage via the cribriform plate to the nasal cavity was severely impaired in both ciliopathy models and associated with chronic rhinitis and olfactory bulb hypoplasia.
The combination of sustained glymphatic transport, impaired solute drainage via the cribriform plate to the nasal cavity and hydrocephalus has not previously been reported in models of MCC ciliopathy. Our data enhance our understanding of how different types of ciliopathies contribute to disruption of CNS fluid homeostasis, manifested in pathologies such as hydrocephalus.
脑积水（由于 CSF 积聚导致脑室增大）是人类纤毛病和基因耗尽多纤毛细胞（MCC）纤毛机制的小鼠模型中的常见发现。然而，MCC 对 CSF 动力学的贡献以及 MCC 功能障碍导致脑积水的机制仍知之甚少。我们研究的目的是检查 MCC 纤毛发生和纤毛产生的 CSF 流缺陷是否会影响包括神经胶质淋巴转运和溶质废物引流在内的中枢神经系统（CNS）液体动态平衡。
我们使用了两种不同的 MCC 纤毛病小鼠模型：MCC 特异性 CEP164 条件性敲除小鼠（FOXJ1-Cre；CEP164（N=10），3 个月大）和 p73 敲除（p73（N=8），5 个月大）小鼠。每种突变体的年龄匹配野生型同窝仔作为对照。使用磁共振成像（MRI）通过 T1 映射对 CSF 输注钆喷酸后的神经胶质淋巴转运和溶质引流进行定量。还评估了脑形态计量学和水通道蛋白 4 表达（AQP4）。在单独的队列中测量颅内压（ICP）。
在两种 MCC 纤毛病模型中，我们发现脑室扩大与正常 ICP 相关。我们表明，患有脑积水的 FOXJ1-Cre；CEP164 小鼠仍表现出持续的神经胶质淋巴转运和沿毛细血管的正常 AQP4 表达。在 p73 小鼠中，神经胶质淋巴转运甚至增加，这与毛细血管周围 AQP4 极化的增加相平行。此外，两种纤毛病模型的筛板至鼻腔的溶质引流均严重受损，并伴有慢性鼻炎和嗅球发育不良。
在 MCC 纤毛病模型中，持续的神经胶质淋巴转运、通过筛板向鼻腔的溶质引流受损以及脑积水的组合以前尚未报道过。我们的数据增强了我们对不同类型纤毛病如何导致中枢神经系统液体动态平衡破坏的理解，这种破坏表现在脑积水等病理中。
