TRPV4 Expression in Hydrocephalic Rat Choroid Plexus

Abstract

Hydrocephalus, also known as “water on the brain,” is a condition characterized by an imbalance in cerebral spinal fluid (CSF) production and/or reabsorption or by a blockage in the CSF circulation resulting in enlarged ventricles of the brain. The main production of CSF comes from the choroid plexus (CP), present in the lateral, third, and fourth ventricles. Composed of a high resistance epithelium that surrounds a network of capillaries, the choroid plexus regulates the transport of ions and water between the ventricles and capillaries through channels in the barrier epithelium, thus controlling the production and movement of CSF. When ions are transported across the epithelium, water follows, suggesting aberrant regulation of ion channels may be one cause of hydrocephalus. The mechano‐ and osmo‐sensitive calcium channel, Transient Receptor Potential Vanilloid‐4 (TRPV4), is a potential regulatory channel which is present in CP epithelia. Utilizing the Wpk rat model, which contains a recessive mutation in TMEM67, we are able to model both rapidly progressing (birth to 3 weeks) and slowly progressing (birth to 1 year) hydrocephalic models (homozygous and heterozygous animals, respectively). These genetic models have the advantage of a naturally occurring hydrocephalus as opposed to the commonly used kaolin infusion model where treatment with the caustic compound ablates the epithelial cells that are under investigation. Treatment of Wpk affected rats with a TRPV4 antagonist was found to ameliorate the hydrocephalus in the rapidly progressing model. Immunohistochemistry of brain tissue slices from the hydrocephalic and wild type animals was utilized to visualize and localize TRPV4. At birth, there is an overexpression of TRPV4 in the CP of the hydrocephalic rats compared to wild type animals, and throughout development the expression continues to increase. In both phenotypes, TRPV4 localized to the apical membrane of the CP. In wild type animals and at birth in hydrocephalic animals there is no detectable TRPV4 expression in the ependymal cells lining the ventricle. However, by 15 days of age in hydrocephalic rats, the ependymal cells do express TRPV4. The increase in TRPV4 expression in hydrocephalic rats, combined with the efficacy of TRPV4 antagonist treatment suggests the calcium channel plays a major role in homeostatic CSF production as well as the formation of hydrocephalus.Support or Funding InformationHydrocephalus Association Innovator Award; Indiana University Collaborative Research Grant and Indiana Clinical and Translational Sciences Institute CTR Award.