TRPV4 in the Choroid Plexus Epithelium: Pathway Analysis and Implications for Cerebrospinal Fluid Production

Hydrocephalus is a disease characterized by an increase in cerebrospinal fluid (CSF) in the ventricles of the brain. This manifests as a result of either overproduction or underabsorption of CSF leading to increases in pressure, swelling and loss of brain matter. Current treatments for this disease include surgical interventions via the introduction of shunts or endoscopic third ventriculostomy, both of which aim to redirect flow of CSF in to another cavity for absorption. Limited pharmacotherapies are available in the treatment of hydrocephalus, and there exists a clinical need for drug therapies, which can ameliorate the pathophysiology associated with hydrocephalus and ventriculomegaly. CSF is produced primarily by the choroid plexus (CP), found in the ventricles of the brain. Composed of a high resistance epithelium surrounding a capillary network, the CP epithelium acts as a barrier, regulating ion transport between the CSF and blood. This thesis describes mechanisms by which TRPV4 may stimulate the transepithelial movement of ions across the CP epithelium, resulting in the production of cerebrospinal fluid. The roles of Calcium-activated potassium channels, calcium-activated chloride channels, sodium-potassium-chloride cotransporters and regulatory enzymes in this mechanistic pathway are explored.