Sustained glymphatic transport and impaired drainage to the nasal cavity observed in multiciliated cell ciliopathies with hydrocephalus

Abstract

Background 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. Methods We used two distinct mouse models of MCC ciliopathy: MCC-specific CEP164 conditional knockout mice (FOXJ1-Cre;CEP164fl/fl (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. Results In both of the two models of MCC ciliopathy we found the ventriculomegaly to be associated with normal ICP. We showed that FOXJ1-Cre;CEP164fl/fl 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. Conclusions 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.

Cross-Vendor Test-Retest Validation of Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS) for Evaluating Glymphatic System Function

“…Therefore, the GS is essential for maintaining cerebral fluid homeostasis across the lifespan. A growing number of studies have demonstrated that the impairment of glymphatic transport was associated with several neurological diseases, including cerebral small vessel disease (cSVD) [3][4][5][6], Alzheimer's disease (AD) [7,8], hydrocephalus [7,9], diabetes [10,11], traumatic brain injury [12,13] and stroke [14,15]. Additionally, GS dysfunction is related to sleep disorder as well as tau and beta-amyloid (Aβ) protein accumulations, which underlie the pathogenesis of cognitive impairment and dementia [16][17][18][19][20][21].…”

Transport Pathways and Kinetics of Cerebrospinal Fluid Tracers in Mouse Brain Observed by Dynamic Contrast-Enhanced MRI

“…Following these foundational DCE-MRI studies in rats, interest in evaluating glymphatic function in mice is rapidly growing, largely due to the availability of genetically manipulated mouse models. 3,6,11,[21][22][23][24][25] Assessing mouse glymphatic function by DCE-MRI has been challenged by the small size of a mouse brain and the limited volume (<20 μL) of fluids that can be delivered intracisternally without significantly altering the intracranial pressure (ICP). 16,26 Early studies on mice used the protocol of administering contrast agent on the bench to allow close monitoring of the infusion process and to visually ensure proper sealing of the infusion site.…”

“…Following these foundational DCE-MRI studies in rats, interest in evaluating the glymphatic function in mice grows rapidly due to the availability of genetically manipulated mouse models 3,6,11,[21][22][23][24][25] . Assessing mouse glymphatic function by DCE-MRI has been challenged by the small size of a mouse brain and the limited volume (<20 μL) of fluids that can be delivered intracisternally without significantly altering the intracranial pressure (ICP) 15,26 .…”

Regulation of brain fluid volumes and pressures: basic principles, intracranial hypertension, ventriculomegaly and hydrocephalus

“…This is not entirely correct. For instance, net movements of CSF through the ventricles are affected to some extent by the beating of cilia on cells of the ependymal lining [ 508 , 509 ]. The effects of cilia are largest close to the lining ependymal layer where they are located relative to those throughout the volume of the CSF containing spaces [ 510 ].…”