title: Aquaporin-4-deficient mice have increased extracellular space without tortuosity change.
abstract: Aquaporin-4 (AQP4) is the major water channel expressed at fluid-tissue barriers throughout the brain and plays a crucial role in cerebral water balance. To assess whether these channels influence brain extracellular space (ECS) under resting physiological conditions, we used the established real-time iontophoresis method with tetramethylammonium (TMA(+)) to measure three diffusion parameters: ECS volume fraction (alpha), tortuosity (lambda), and TMA(+) loss (k'). In vivo measurements were performed in the somatosensory cortex of AQP4-deficient (AQP4(-/-)) mice and wild-type controls with matched age. Mice lacking AQP4 showed a 28% increase in alpha (0.23 +/- 0.007 vs 0.18 +/- 0.003) with no differences in lambda (1.62 +/- 0.04 vs 1.61 +/- 0.02) and k' (0.0045 +/- 0.0001 vs 0.0031 +/- 0.0009 s(-1)). Additional recordings in brain slices showed similarly elevated alpha in AQP4(-/-) mice, and no differences in lambda and k' between the two genotypes. This is the first direct comparison of ECS properties in adult mice lacking AQP4 water channels with wild-type animals and demonstrates a significant enlargement of the volume fraction but no difference in hindrance to TMA(+) diffusion, expressed as tortuosity. These findings provide direct evidence for involvement of AQP4 in modulation of the ECS volume fraction and provide a basis for future modeling of water and ion transport in the CNS.
authors.affiliation: Department of Neurosurgery and Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, California 94110, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yao
authors.forename: Sabina
authors.initials: S
authors.lastname: Hrabetová
authors.forename: Charles
authors.initials: C
authors.lastname: Nicholson
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Manley
mesh_terms: D000367:Age Factors; D000818:Animals; D051401:Aquaporin 4 / Q000172:deficiency*; D002540:Cerebral Cortex / Q000166:cytology* / Q000378:metabolism; D004058:Diffusion; D005110:Extracellular Space / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000644:Quaternary Ammonium Compounds / Q000378:metabolism
chemical_list: D051401:Aquaporin 4; D000644:Quaternary Ammonium Compounds; C027917:tetramethylammonium