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Test of the ‘glymphatic’ hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma

  1. Alex J Smith  Is a corresponding author
  2. Xiaoming Yao
  3. James A Dix
  4. Byung-Ju Jin
  5. Alan S Verkman
  1. University of California, San Francisco, United States
Research Article
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Cite this article as: eLife 2017;6:e27679 doi: 10.7554/eLife.27679

Abstract

Transport of solutes through brain involves diffusion and convection. The importance of convective flow in the subarachnoid and paravascular spaces has long been recognized; a recently proposed ‘glymphatic’ clearance mechanism additionally suggests that aquaporin-4 (AQP4) water channels facilitate convective transport through brain parenchyma. Here, the major experimental underpinnings of the glymphatic mechanism were re-examined by measurements of solute movement in mouse brain following intracisternal or intraparenchymal solute injection. We found that: (i) transport of fluorescent dextrans in brain parenchyma depended on dextran size in a manner consistent with diffusive rather than convective transport; (ii) transport of dextrans in the parenchymal extracellular space, measured by 2-photon fluorescence recovery after photobleaching, was not affected just after cardiorespiratory arrest; and (iii) Aqp4 gene deletion did not impair transport of fluorescent solutes from sub-arachnoid space to brain. Our results do not support the proposed glymphatic mechanism of convective solute transport in brain parenchyma.

Article and author information

Author details

  1. Alex J Smith

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    For correspondence
    alex.smith@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3034-9137
  2. Xiaoming Yao

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. James A Dix

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Byung-Ju Jin

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Alan S Verkman

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institutes of Health (EB00415)

  • Alan S Verkman

Guthy-Jackson Charitable Foundation

  • Alan S Verkman

National Institutes of Health (EY13574)

  • Alan S Verkman

National Institutes of Health (DK72517)

  • Alan S Verkman

National Institutes of Health (DK35124)

  • Alan S Verkman

National Institutes of Health (DK101273)

  • Alan S Verkman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol #AN108511 of the University of California San Francisco. All surgery was performed under avertin or anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. John Huguenard, Stanford University School of Medicine, United States

Publication history

  1. Received: April 17, 2017
  2. Accepted: August 18, 2017
  3. Accepted Manuscript published: August 21, 2017 (version 1)
  4. Version of Record published: August 31, 2017 (version 2)

Copyright

© 2017, Smith et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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