Aberrant adenosine Areceptor signaling in the choroid plexus drives CSF hypersecretion and ventriculomegaly in hydrocephalus.

Abstract

Hydrocephalus is a common and serious neuropathological condition characterized by disrupted cerebrospinal fluid (CSF) circulation, which lacks effective pharmacotherapy. Here, we demonstrate that adenosine Areceptor (AR) signaling in the choroid plexus (ChP) is a trigger of hydrocephalus. Adenosine levels are increased in the CSF of hydrocephalus patients and mice, together with elevated ChP-AR density. Accordingly, continued infusion of adenosine for 14 days or transgenic ChP-AR overexpression is sufficient to drive CSF hypersecretion and ventriculomegaly. Conversely, selective knockdown of ChP-AR reduces CSF production and ameliorates CSF hypersecretion and ventriculomegaly induced by autologous blood and kaolin. Furthermore, we unveil ChP-AR signaling as a molecular mechanism linking brain insults with CSF hypersecretion through parallel PI3K/Akt-dependent activation of SPAK phosphorylation and NF-κB-dependent transcriptional regulation of ATP1A2. Lastly, the AR antagonist KW6002 protects against hydrocephalus induced by autologous blood and kaolin, offering a novel treatment for hydrocephalus by repurposing the FDA-approved AR antagonist istradefylline.