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

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.

Reviewing Editor

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

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.

Version 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.

Metrics

  • 4,978
    views
  • 976
    downloads
  • 235
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Alex J Smith
  2. Xiaoming Yao
  3. James A Dix
  4. Byung-Ju Jin
  5. Alan S Verkman
(2017)
Test of the ‘glymphatic’ hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma
eLife 6:e27679.
https://doi.org/10.7554/eLife.27679

Share this article

https://doi.org/10.7554/eLife.27679

Further reading

    1. Neuroscience
    Songyao Zhang, Tuo Zhang ... Tianming Liu
    Research Article

    Cortical folding is an important feature of primate brains that plays a crucial role in various cognitive and behavioral processes. Extensive research has revealed both similarities and differences in folding morphology and brain function among primates including macaque and human. The folding morphology is the basis of brain function, making cross-species studies on folding morphology important for understanding brain function and species evolution. However, prior studies on cross-species folding morphology mainly focused on partial regions of the cortex instead of the entire brain. Previously, our research defined a whole-brain landmark based on folding morphology: the gyral peak. It was found to exist stably across individuals and ages in both human and macaque brains. Shared and unique gyral peaks in human and macaque are identified in this study, and their similarities and differences in spatial distribution, anatomical morphology, and functional connectivity were also dicussed.

    1. Neuroscience
    Avani Koparkar, Timothy L Warren ... Lena Veit
    Research Article

    Complex skills like speech and dance are composed of ordered sequences of simpler elements, but the neuronal basis for the syntactic ordering of actions is poorly understood. Birdsong is a learned vocal behavior composed of syntactically ordered syllables, controlled in part by the songbird premotor nucleus HVC (proper name). Here, we test whether one of HVC’s recurrent inputs, mMAN (medial magnocellular nucleus of the anterior nidopallium), contributes to sequencing in adult male Bengalese finches (Lonchura striata domestica). Bengalese finch song includes several patterns: (1) chunks, comprising stereotyped syllable sequences; (2) branch points, where a given syllable can be followed probabilistically by multiple syllables; and (3) repeat phrases, where individual syllables are repeated variable numbers of times. We found that following bilateral lesions of mMAN, acoustic structure of syllables remained largely intact, but sequencing became more variable, as evidenced by ‘breaks’ in previously stereotyped chunks, increased uncertainty at branch points, and increased variability in repeat numbers. Our results show that mMAN contributes to the variable sequencing of vocal elements in Bengalese finch song and demonstrate the influence of recurrent projections to HVC. Furthermore, they highlight the utility of species with complex syntax in investigating neuronal control of ordered sequences.