Aquaporin-4-dependent glymphatic solute transport in the rodent brain
- University of Rochester Medical Center, United States
- University of Copenhagen, Denmark
- Nanjing Medical University, China
- RIKEN, Japan
- The University of North Carolina at Chapel Hill, United States
- Oregon Health and Science University, United States
- Haukeland University Hospital, Norway
- Lund University, Sweden
- Keio University, Japan
- University of Rochester, United States
Abstract
The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-β. Influx of cerebrospinal fluid(CSF) depends upon the expression and perivascular localization of the astroglial water channel aquaporin-4(AQP4). Prompted by a recent failure to find an effect of Aqp4 knock-out(KO) on CSF and interstitial fluid(ISF) tracer transport, five groups re-examined the importance of AQP4 in glymphatic transport. We concur that CSF influx is higher in wildtype mice than in four different Aqp4 KO lines and in one line that lacks perivascular AQP4(Snta1 KO). Meta-analysis of all studies demonstrated a significant decrease in tracer transport in KO mice and rats compared to controls. Meta-regression indicated that anesthesia, age, and tracer delivery explain the opposing results. We also report that intrastriatal injections suppress glymphatic function. This validates the role of AQP4 in accordance with the glymphatic system and shows that invasive procedures should not be utilized.
Data availability
All data generated or analysed during this study are included in the manuscript.
Article and author information
Author details
Funding
National Institutes of Health (NS100366)
- Maiken Nedergaard
Japan Society for the Promotion of Science (18H02606)
- Masato Yasui
Human Frontier Science Program (RGP0036/2014)
- Hajime Hirase
Japan Society for the Promotion of Science (Core-to-Core Program)
- Hajime Hirase
Lundbeckfonden (Visiting Professorship)
- Hajime Hirase
Knut och Alice Wallenbergs Stiftelse (Helse Vet)
- Alexander S Thrane
National Institutes of Health (NS061800)
- Aravind Asokan
National Institutes of Health (AG048769)
- Maiken Nedergaard
National Institutes of Health (AG054456)
- Jeffrey J Iliff
National Institutes of Health (NS099371)
- Aravind Asokan
National Institutes of Health (HL089221)
- Aravind Asokan
National Institutes of Health (NS089709)
- Jeffrey J Iliff
National Institutes of Health (NS078394)
- Maiken Nedergaard
National Institutes of Health (AG048769)
- Maiken Nedergaard
Japan Society for the Promotion of Science (18K14859)
- Hiromu Monai
Japan Society for the Promotion of Science (16H01888)
- Hajime Hirase
Japan Society for the Promotion of Science (18H05150)
- Hajime Hirase
Japan Society for the Promotion of Science (17K19637)
- Yoichiro Abe
Japan Society for the Promotion of Science (16H05134)
- Yoichiro Abe
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (IACUC-1601106), Wako Animal Experiment Committee, RIKEN (Recombinant DNA experimentation protocol: 2016-038; Animal experimentation protocol: H29-2-227), The University of North Carolina at Chapel Hill Institutional Animal Care and Use Committee (protocol 15-109), the University Committee on Animal Resources of the University of Rochester (protocol 2011-023), and the IACUC of Oregon Health and Science University (protocol IP00000394). All experiments were performed in accordance with the approved guidelines and regulations. All efforts were made to minimize animal suffering and to reduce the number of animals used for the experiments.
Copyright
© 2018, Mestre 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
-
- 11,644
- views
-
- 2,101
- downloads
-
- 428
- 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)
Aquaporin-4-dependent glymphatic solute transport in the rodent brain
eLife 7:e40070.
https://doi.org/10.7554/eLife.40070
Further reading
-
- Neuroscience
Brain states fluctuate between exploratory and consummatory phases of behavior. These state changes affect both internal computation and the organism’s responses to sensory inputs. Understanding neuronal mechanisms supporting exploratory and consummatory states and their switching requires experimental control of behavioral shifts and collecting sufficient amounts of brain data. To achieve this goal, we developed the ThermoMaze, which exploits the animal’s natural warmth-seeking homeostatic behavior. By decreasing the floor temperature and selectively heating unmarked areas, we observed that mice avoided the aversive state by exploring the maze and finding the warm spot. In its design, the ThermoMaze is analogous to the widely used water maze but without the inconvenience of a wet environment and, therefore, allows the collection of physiological data in many trials. We combined the ThermoMaze with electrophysiology recording, and report that spiking activity of hippocampal CA1 neurons during sharp-wave ripple events encode the position of mice. Thus, place-specific firing is not confined to locomotion and associated theta oscillations but persist during waking immobility and sleep at the same location. The ThermoMaze will allow for detailed studies of brain correlates of immobility, preparatory–consummatory transitions, and open new options for studying behavior-mediated temperature homeostasis.
-
- Neuroscience
As the global population ages, the prevalence of neurodegenerative disorders is fast increasing. This neurodegeneration as well as other central nervous system (CNS) injuries cause permanent disabilities. Thus, generation of new neurons is the rosetta stone in contemporary neuroscience. Glial cells support CNS homeostasis through evolutionary conserved mechanisms. Upon damage, glial cells activate an immune and inflammatory response to clear the injury site from debris and proliferate to restore cell number. This glial regenerative response (GRR) is mediated by the neuropil-associated glia (NG) in Drosophila, equivalent to vertebrate astrocytes, oligodendrocytes (OL), and oligodendrocyte progenitor cells (OPCs). Here, we examine the contribution of NG lineages and the GRR in response to injury. The results indicate that NG exchanges identities between ensheathing glia (EG) and astrocyte-like glia (ALG). Additionally, we found that NG cells undergo transdifferentiation to yield neurons. Moreover, this transdifferentiation increases in injury conditions. Thus, these data demonstrate that glial cells are able to generate new neurons through direct transdifferentiation. The present work makes a fundamental contribution to the CNS regeneration field and describes a new physiological mechanism to generate new neurons.
