Accelerated progression of kaolin-induced hydrocephalus in aquaporin-4-deficient mice

Orin Bloch, Kurtis I. Auguste, Geoffrey T. Manley, A. S. Verkman

Research output: Contribution to journalArticle

137 Scopus citations

Abstract

Hydrocephalus is caused by an imbalance in cerebrospinal fluid (CSF) production and absorption, resulting in excess ventricular fluid accumulation and neurologic impairment. Current therapy for hydrocephalus involves surgical diversion of excess ventricular fluid. The water-transporting protein aquaporin-4 (AQP4) is expressed at the brain-CSF and blood-brain barriers. Here, we provide evidence for AQP4-facilitated CSF absorption in hydrocephalus by a transparenchymal pathway into the cerebral vasculature. A mouse model of obstructive hydrocephalus was created by injecting kaolin (2.5 mg/mouse) into the cisterna magna. Intracranial pressure (ICP) was ∼5 mm Hg and ventricular size <0.3 mm3 in control mice. Lateral ventricle volume increased to 3.7±0.5 and 5.1±0.5 mm3 in AQP4 null mice at 3 and 5 days after injection, respectively, significantly greater than 2.6±0.3 and 3.5±0.5 mm3 in wildtype mice (P<0.005). The corresponding ICP was 22±2 mm Hg at 3 days in AQP4 null mice, significantly greater than 14±1 mm Hg in wildtype mice (P<0.005). Brain parenchymal water content increased by 2% to 3% by 3 days, corresponding to ∼50 μL of fluid, indicating backflow of CSF from the ventricle into the parenchymal extracellular space. A multi-compartment model of hydrocephalus based on experimental data from wildtype mice accurately reproduced the greater severity of hydrocephalus in AQP4 null mice, and predicted a much reduced severity if AQP4 expression/function were increased. Our results indicate a significant role for AQP4-mediated transparenchymal CSF absorption in hydrocephalus and provide a rational basis for evaluation of AQP4 induction as a nonsurgical therapy for hydrocephalus.

Original languageEnglish (US)
Pages (from-to)1527-1537
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume26
Issue number12
DOIs
StatePublished - Dec 8 2006
Externally publishedYes

Keywords

  • AQP4
  • Blood-brain barrier
  • Hydrocephalus
  • Interstitial edema
  • Water channel

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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