title: Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1.
abstract: Aquaporin-1 (AQP1) is a water channel expressed strongly at the ventricular-facing surface of choroid plexus epithelium. We developed novel methods to compare water permeability in isolated choroid plexus of wild-type vs. AQP1 null mice, as well as intracranial pressure (ICP) and cerebrospinal fluid (CSF) production and absorption. Osmotically induced water transport was rapid in choroid plexus from wild-type mice and reduced by fivefold by AQP1 deletion. AQP1 deletion did not affect choroid plexus size or structure. By stereotaxic puncture of the lateral ventricle with a microneedle, ICP was 9.5 +/- 1.4 cm H2O in wild-type mice and 4.2 +/- 0.4 cm H2O in AQP1 null mice. CSF production, an isosmolar fluid secretion process, was measured by a dye dilution method involving fluid collections using a second microneedle introduced into the cisterna magna. CSF production in wild-type mice was (in microl min(-1)) 0.37 +/- 0.04 (control), 0.16 +/- 0.03 (acetazolamide-treated), and 1.14 +/- 0.15 (forskolin-treated), and reduced by approximately 25% in AQP1 null mice. Pressure-dependent CSF outflow, measured from steady-state ICP at different ventricular infusion rates, was not affected by AQP1 deletion. In a model of focal brain injury, AQP1 null mice had remarkably reduced ICP and improved survival compared with wild-type mice. The reduced ICP and CSF production in AQP1 null mice provides direct functional evidence for the involvement of AQP1 in CSF dynamics, suggesting AQP1 inhibition as a novel option for therapy of elevated ICP.
authors.affiliation: Department of Neurosurgery, University of California, San Francisco, California 94110, USA.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Oshio
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Yaunlin
authors.initials: Y
authors.lastname: Song
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Manley
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D051398:Aquaporin 1; D020346:Aquaporins / Q000096:biosynthesis / Q000172:deficiency* / Q000502:physiology*; D001929:Brain Edema / Q000382:microbiology / Q000473:pathology; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D002831:Choroid Plexus / Q000737:chemistry*; D004195:Disease Models, Animal; D007427:Intracranial Pressure / Q000502:physiology*; D016920:Meningitis, Bacterial; D008586:Meningitis, Pneumococcal / Q000150:complications; D051379:Mice; D013296:Streptococcus pneumoniae / Q000472:pathogenicity
chemical_list: C496021:Aqp1 protein, mouse; D020346:Aquaporins; D051398:Aquaporin 1