Sporadic obstructive hydrocephalus in Aqp4 null mice

Abstract

Aquaporin-4 (Aqp4) is a water transport protein expressed in glia and ependymocytes in brain. We report here the unexpected occurrence of severe obstructive hydrocephalus in a random subset of Aqp4 knockout mice. Of 612 Aqp4 knockout mice produced by heterozygote–heterozygote or knockout–knockout breedings, 9.6% of offspring manifested progressive encephalomegaly. Encephalomegaly was never seen in wild-type or Aqp4 heterozygous mice. Examination of the subset encephalomegalic mice revealed marked triventricular hydrocephalus (lateral ventricle size ~500 mm3), elevated intracranial pressure (19 ± 3 vs. 6.1 ± 0.6 mm Hg), and death by age 6 weeks, with a median survival of 28 days. Intraventricular dye injection studies revealed total obstruction of the cerebral aqueduct. Evans blue extravasation studies indicated an intact blood–brain barrier in the hydrocephalic mice. Brain histology revealed reduced ventricular size and ependymocyte disorganization in some nonhydrocephalic Aqp4 null mice. Our studies establish Aqp4 deletion as a predisposing factor for the development of congenital obstructive hydrocephalus in mice. We suggest that AQP4 polymorphisms might also contribute to the development of aqueduct stenosis in humans.

Deletion of aquaporin‐4 changes the perivascular glial protein scaffold without disrupting the brain endothelial barrier

“…Reports conflict as to whether AQP4 modulates BBB integrity (Feng et al, 2009;Saadoun et al, 2009;Zhou et al, 2008). Our electron microscopic analysis confirmed the presence of pericytes and endothelial tight junctions in Aqp4 mutant mice, and immunoblots revealed comparable levels of the tight junction proteins claudin-5, occludin and ZO-1 in the two genotypes.…”

“…Our results were obtained in C57BL/6J mice and are in agreement with those obtained in CD1 mice by Saadoun et al (2009), but contrast those of Zhou et al (2008), also using CD1 mice. Notably, the former group failed to replicate BBB dysfunction in the mouse strain used by Zhou et al (Feng et al, 2009). Moreover, BBB permeability was found to be normal in a-syn 2/2 mice (Zeynalov et al, 2008).…”

“…However, in more recent studies, Aqp4 deletion did not affect capillary ultrastructure and BBB permeability for horseradish peroxidase (HRP) (Saadoun et al, 2009) or Evans Blue (Feng et al, 2009). The aim of this study was to use a different line of…”

Hydrocephalus: the role of cerebral aquaporin-4 channels and computational modeling considerations of cerebrospinal fluid

“…116 Feng et al experimented with Aqp4-knockout mice, which produced a sporadic 9.6% rate of encephalomegaly (triventricular hydrocephalus with elevated intracranial pressure [ICP]) by the age of 6 weeks, linking AQP4 to the development of congenital hydrocephalus in mice. 34 Bloch et al found accelerated progression of kaolin-induced hydrocephalus in Aqp4-knockout mice when compared with controls, with a significantly higher lateral ventricle volume and ICP measurements as early as 3 days after injection, suggesting that the lack of AQP4 channels is related to the development of hydrocephalus.…”

Expression of Aquaporin 1 and 4 in a Congenital Hydrocephalus Rat Model

“…6,24,25 Approximately 10% of AQP4 2/2 mice exhibit congenital hydrocephalus, and experimentally induced hydrocephalus is more severe in these animals compared with wild-type mice. 26,27 Because AQP4 facilitates brain water absorption in the cerebral microvasculature, inadequate expression of this protein may be a predisposing factor in hydrocephalus.…”