Flow blockage disrupts cilia-driven fluid transport in the epileptic brain

• Published in: Acta neuropathologica Vol. 144; no. 4; pp. 691 - 706
• Main Authors: Faubel, Regina J., Santos Canellas, Veronica S., Gaesser, Jenna, Beluk, Nancy H., Feinstein, Tim N., Wang, Yong, Yankova, Maya, Karunakaran, Kalyani B., King, Stephen M., Ganapathiraju, Madhavi K., Lo, Cecilia W.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-10-2022; Springer; Springer Nature B.V
• Subjects: Age; Anesthesia; Animals; Brain; Cerebrospinal fluid; Cilia; Cilia - genetics; Convulsions & seizures; Epilepsy; Epileptic Syndromes; Etiology; Evolutionary conservation; Fluid flow; Fluorescent indicators; Genetic aspects; Humans; Medical research; Medicine; Medicine & Public Health; Medicine, Experimental; Mice; Mice, Knockout; Neurodevelopmental disorders; Neurosciences; Original Paper; Pathology; Physiology; Protein Serine-Threonine Kinases - genetics; Seizures; Seizures (Medicine); Spasms, Infantile; Structure-function relationships; Therapeutic targets; Ventricle; Ventricles (cerebral); Homeostasis; Seizure; Cerebrospinal fluid; Transport; Epilepsy; Cilia
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-022-02463-y

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.