Disrupted Choroid Plexus Calcium Signaling Generates Decompensated Hydrocephalus in Mouse Models of Pediatric IVH. (16th November 2020)

• Record Type: Journal Article
• Authors: Sadegh, Cameron; Xu, Huixin; Sutin, Jason; Benedict, Michaela; Shipley, Frederick; Warf, Benjamin C; Andermann, Mark; Lehtinen, Maria K
• Is Part Of: Neurosurgery. Volume 67(2010)Supplement 1
• Publication Date: 2020-11-16
• Subjects: Nervous system -- Surgery -- Periodicals; 617.48005
• DOI: 10.1093/neuros/nyaa447_574
• Languages: English
• ISSNs: 0148-396X

Abstract

Abstract: INTRODUCTION: Existing rodent models of prenatal or early postnatal intraventricular hemorrhage (IVH) develop mild ventriculomegaly, recapitulating only the earliest stage of post-hemorrhagic hydrocephalus (PHH). Here we aim to develop improved mouse models of pediatric IVH as well as implement existing clinical diagnostic tools to better characterize the biophysical severity of PHH. We use these improved models to identify choroid plexus (ChP) epithelial calcium signaling as an essential mechanism for increasing trans-epithelial potassium transport and for limiting the severity of ventriculomegaly. METHODS: Prenatal and early postnatal IVH were modeled at embryonic day 14.5 and postnatal day 4, respectively, by rapid intraventricular injection of unmodified, age-matched blood from living mouse donors. Ventricle size was evaluated at 2–3 weeks using MRI. Intracranial biophysical measurements (intracranial pressure [ICP], intracranial compliance, and total capacity for CSF reabsorption/efflux) at age 8–9 weeks were derived from a modified single-catheter constant infusion test. Live imaging of embryonic ChP explants from FoxJ1::Gcamp6f transgenic mice was utilized to evaluate the effects of calcium disrupting reagents on the epithelial responses to blood products. RESULTS: Both prenatal and early postnatal models of pediatric IVH approximately double the ventricular volume, with decreased intracranial compliance, stable ICP, and increased capacity for CSF efflux, consistent with the asymptomatic, clinically compensated state. During live imaging of embryonic ChP explants, pharmacological disruption of calcium release machinery prevents a rapid epithelial calcium response in the presence of blood products, and inhibits the phosphorylation of a critical bidirectional potassium and water cotransporter. When applied in vivo, disrupted ChP epithelia generate a decompensated model of PHH, accompanied by severe ventriculomegaly and reduced CSF efflux that more closely resembles symptomatic hydrocephalus. CONCLUSION: We developed models of compensated and decompensated pediatric PHH and describe tools to assess intracranial biophysical changes in these mice. The data highlight the requirement of rapid calcium signaling by ChP epithelia to improve potassium and water cotransport for the regulation of ventricle volume after IVH. Together, these insights provide molecular targets for the improved treatment of PHH.