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The Journal of Neuroscience, May 21, 2008, 28(21):5460-5464; doi:10.1523/JNEUROSCI.0257-08.2008

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Brief Communications
Aquaporin-4-Deficient Mice Have Increased Extracellular Space without Tortuosity Change

Xiaoming Yao,^1,2 Sabina Hrabtová,^3,4 Charles Nicholson,³ and Geoffrey T. Manley^1,2

¹Department of Neurosurgery and ²Brain and Spinal Injury Center, University of California, San Francisco, San Francisco, California 94110, ³Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, and ⁴Department of Anatomy and Cell Biology, Downstate Medical Center, State University of New York, Brooklyn, New York 11203

Correspondence should be addressed to Dr. Geoffrey T. Manley, Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Avenue, Room 101, San Francisco, CA 94110. Email: manley{at}itsa.ucsf.edu

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 (), tortuosity (), 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 (0.23 ± 0.007 vs 0.18 ± 0.003) with no differences in (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 in AQP4^–/– mice, and no differences in 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.

Key words: aquaporin-4; diffusion; tetramethylammonium; volume fraction; seizure; water transport

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Received Jan. 18, 2008; revised April 10, 2008; accepted April 14, 2008.

Correspondence should be addressed to Dr. Geoffrey T. Manley, Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Avenue, Room 101, San Francisco, CA 94110. Email: manley{at}itsa.ucsf.edu

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