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

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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.

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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.

"This ORCID iD identifies the author of this article:" 0000-0002-3034-9137
Xiaoming Yao

Department of Medicine, University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
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.
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.
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.

Copyright

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.