Characterizing the Expression of TRPV4 in the Choroid Plexus Epithelia as a Prospective Component in the Development of Hydrocephalus in the Gas8GT Juvenile Mouse Model

Abstract

Maintenance of homeostatic cerebrospinal fluid (CSF) secretion and absorption is essential for basic neurologic function. The choroid plexus epithelia, which is thought to 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 such as hydrocephalus, where this homeostasis is disrupted, patients often experience symptoms such as cognitive impairment, motor/stability issues, and incontinence, among others. Current treatment for hydrocephalus is limited to surgically invasive shunting procedures which often fail and need revising – particularly in pediatric cases. In order to study the mechanism of this disease, a knock out mouse line of the Growth Arrest Specific 8 (Gas8) allele was generated. Loss of function of the Gas8 allele induces ciliopathy similar to Primary Ciliary Dyskinesia (PCD) in humans, with one of the symptoms being severe perinatal hydrocephalus. The disease progression in the mutant (−/−) mice is from postnatal day 0 (P0) to postnatal day 12–16 (P12–16), which makes this an excellent model to study pediatric/juvenile hydrocephalus. 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. Consistent with other studies, TRPV4 is localized to the apical membrane of the CP epithelial tissue in the Wild Type Gas8 mice. Preliminary data on the juvenile Gas8 mice indicate that TRPV4 is overexpressed in CP epithelia, ependymal cells and in the sub‐ventricular zone in the mutants as their hydrocephalus progresses as compared to the wild type (+/+) and heterozygous (+/−) animals. This suggests that antagonistic compounds of the TRPV4 channel have the potential to reduce hydrocephalus in the Gas8 model. 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.Support or Funding InformationFunding: Grants from the Hydrocephalus Association and the Department of Defense Office of the Congressionally Directed Medical Research Programs (CDMRP).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.