Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C028

Oral Communications

Characterizing the expression of TRPV4 in the choroid plexus epithelia as a prospective component in the development of hydrocephalus.

A. E. Hochstetler1, D. Preston1, S. Simpson1, N. Berbari1, B. Blazer-Yost1,2

1. Biology, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States. 2. Cellular and Integrative Physiology/Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States.


Homeostatic maintenance of cerebrospinal fluid (CSF) secretion and absorption is essential for basic neurologic function. The choroid plexus epithelia, which produce the majority of the CSF, are among the most secretory of all epithelia. However, the control of this secretory process is poorly described. In diseased states like hydrocephalus, where this homeostasis is disrupted, patients often experience symptoms such as cognitive impairment, motor/stability issues, and incontinence. Current treatment for hydrocephalus is limited to surgically invasive shunting procedures which often fail and need revision - particularly in pediatric cases. We have used several preclinical models to study the mechanisms of CSF regulation. In addition to a porcine choroid plexus epithelial cell line, two rodent ciliopathy models were used - the W-WPK rat and the GAS8 mouse. The W-WPK rat is analogous to Meckel-Gruber Syndrome, and the GAS8 mouse has a phenotype similar to Primary Ciliary Dyskinesia. Both of these models present with severe perinatal hydrocephalus in the mutant null pups. It is believed that one of the mechanisms of pediatric hydrocephalus is the overproduction of CSF by the choroid plexus (CP) epithelial cells that line the ventricles of the brain. The protein of interest to this research is the non-specific cation channel, Transient Receptor Potential Vanilloid 4 (TRPV4), which has been shown to be activated by multiple stimuli including osmotic and pressure changes as well as by prostanoid metabolites. Activation of TRPV4 results in Ca2+ influx through the channel resulting in changes in intracellular signaling including the secondary activation of Ca2+-stimulated ion transporters. In both models, TRPV4 is localized to the apical membrane of the CP epithelial tissue in the Wild Type pup. Preliminary data indicate that TRPV4 is overexpressed in CP epithelia, ependymal cells and in the sub ventricular zone in the mutant null pups of both models as their hydrocephalus progresses when compared to the wild type and heterozygous animals. Furthermore, in the rat pups, treatment of an antagonist compound of TRPV4 (RN 1734, administered i.p. once daily for seven days) reduced the hydrocephalus in the affected animals (via MRI ventricular volume quantification) and diminished TRPV4 expression. This suggests that antagonistic compounds of the TRPV4 channel have the potential to reduce hydrocephalus in these models. Successfully targeting the molecular mechanisms for hydrocephalus in rodent models can provide a promising base for preclinical studies aimed at developing pharmaceutical agents to treat this disease.

Where applicable, experiments conform with Society ethical requirements