Hydrocephalus is a highly prevalent neurological disorder characterized by elevated levels of cerebrospinal fluid (CSF) in the brain and subsequent enlargement of the lateral ventricles. Currently, the only treatment for this disorder is recurrent neurosurgery to insert and revise shunts that drain the CSF. To develop better treatments for hydrocephalus, an understanding of the cellular, histological and behavioral changes that occur in the pathogenesis of hydrocephalus is required. To this end, we have developed a novel model of hydrocephalus, called the Ro1 model, which was created using the tetracycline inducible system to direct Ro1 expression to cells expressing glial fibrillary acidic protein. This model is unique in that hydrocephalus can be induced at any age with complete penetrance and without interfering pathologies, enabling the investigation of the earliest pathological changes that lead to hydrocephalus. Also, the specific activation of a G-protein coupled receptor (the Ro1 receptor) in a specific subset of cells makes investigating signaling pathways involved in hydrocephalus tractable. We discovered that the earliest pathological changes in this model were ventriculomegaly and disorganization of the ependymal lining of the aqueduct of Sylvius. Thinning and eventual denudation of the ependymal lining was subsequent to ventriculomegaly. Additionally, following severe ventriculomegaly, periventricular edema and areas of the ventricular walls void of microvilli were observed. Stenosis of the aqueduct of Sylvius was not present even with severe ventriculomegaly, suggesting that the Ro1 model represents a model of communicating hydrocephalus. Interestingly, even with severe ventriculomegaly, there were no behavioral changes, possibly due to compensation of the brain tissue due to the slow progression of hydrocephalus in this model. These data provide insight into the earliest cellular, histological and behavioral changes in the pathogenesis of hydrocephalus, which may lead to the development of therapeutic treatments for this disorder
