Regulation of Choroid Plexus Bicarbonate Transporters Following Intraventricular Hemorrhage in Mice.

Abstract

Posthemorrhagic hydrocephalus is a severe complication to intraventricular hemorrhage. The condition results in enlarged brain ventricles and increased intracranial pressure due to accumulation of cerebrospinal fluid (CSF). In this study, two mouse models of intraventricular hemorrhage were investigated: injection of lysed red blood cells (LRBC) and injection of autologous full blood. CSF secretion and ventricular volume were assessed using ventriculo-cisternal perfusion and magnetic resonance imaging (MRI), while molecular and biochemical responses were analyzed by immunoblotting, RT-qPCR, flame photometry, and blood-gas measurements. LRBC injection induced a transient change in choroid plexus bicarbonate transporter expression, as the protein-abundance of Ncbe, a basolateral sodium-bicarbonate transporter, was reduced by 23% after 24 h but increased by 17% after 48 h. Injection with full blood transiently increased mRNA levels of the basolateral sodium-bicarbonate transporter NBCn1 and Ncbe without altering protein expression. The luminal electrogenic sodium: bicarbonate transporter, NBCe2, was unaffected both at the RNA and protein level. Both models were validated using ventriculo-cisternal perfusion demonstrating an increase in CSF volume by 70% in the IVH model after 24 h and 73% in the LRBC model after 3 days. No effect on secretion rate of CSF was detected. Additionally, in the LRBC model MRI was used to assess the time-course of brain ventricle size following hemorrhage. Here, an overall volume increase of 30% was found in the hemorrhage-induced mice compared to the control. These results demonstrate that both LRBC and full-blood injections can induce ventricular enlargement in mice, but through different molecular responses. Neither model reproduced sustained CSF hypersecretion, underscoring that murine models of intraventricular hemorrhage display a milder form of pathophysiology compared to e.g. rats.