Loss of aquaporin-4 results in glymphatic system dysfunction via brain-wide interstitial fluid stagnation
- University of Copenhagen, Denmark
- University of Rochester Medical Center, United States
- University of Pennsylvania, United States
Abstract
The glymphatic system is a fluid transport network of cerebrospinal fluid (CSF) entering the brain along arterial perivascular spaces, exchanging with interstitial fluid (ISF), ultimately establishing directional clearance of interstitial solutes. CSF transport is facilitated by the expression of aquaporin-4 (AQP4) water channels on the perivascular endfeet of astrocytes. Mice with genetic deletion of AQP4 (AQP4 KO) exhibit abnormalities in the brain structure and molecular water transport. Yet, no studies have systematically examined how these abnormalities in structure and water transport correlate with glymphatic function. Here we used high-resolution 3D magnetic resonance (MR) non-contrast cisternography, diffusion-weighted MR imaging (MR-DWI) along with intravoxel-incoherent motion (IVIM) DWI, while evaluating glymphatic function using a standard dynamic contrast-enhanced MR imaging to better understand how water transport and glymphatic function is disrupted after genetic deletion of AQP4. AQP4 KO mice had larger interstitial spaces and total brain volumes resulting in higher water content and reduced CSF space volumes, despite similar CSF production rates and vascular density compared to wildtype mice. The larger interstitial fluid volume likely resulted in increased slow but not fast MR diffusion measures and coincided with reduced glymphatic influx. This markedly altered brain fluid transport in AQP4 KO mice may result from a reduction in glymphatic clearance, leading to enlargement and stagnation of fluid in the interstitial space. Overall, diffusion MR is a useful tool to evaluate glymphatic function and may serve as valuable translational biomarker to study glymphatics in human disease.
Data availability
Entire data from the paper is available in the .xls data file attached. The attached data file is subdivided into separate sheets, each for a single experiment and accompanied with respective heading and descriptions, and provides the possibility of replicating all figures and statistics. A summary of data is presented in the tables and figures within the paper.A detailed description of an author algorithm for CSF space segmentation from 3D-CISS images, as well as DWI analysis, is provided in the Materials and Methods section (page 14 onward). Submission of the CSF space segmentation code in Matlab will be performed during the submission of a separate technical paper and will include a supplementary evaluation of this authorship algorithm using a large data set. A preliminary evaluation of the algorithm was presented during ESMRMB 2021 conference: Gomolka RS, Nedergaard M, Mori Y. CSF space volumetry using 3D-CISS in Aqp4-deficient mice - quantitative analysis and technical advances. ESMRMB 2021 Online 38th Annual Scientific Meeting 7-9 October 2021. Book of Abstracts ESMRMB 2021. Magnetic Resonance Materials in Physics, Biology, and Medicine; 34: S95-6. [Poster, abstract]. Therefore, publishing the code in Github (or else) will take place parallel to submitting a separate technical report on the algorithm.
Article and author information
Author details
Natalie Linea Hauglund
Funding
Lundbeckfonden (R386--2021--165)
- Maiken Nedergaard
Novo Nordisk Fonden (NNF20OC0066419)
- Maiken Nedergaard
National Institutes of Health (R01AT011439)
- Maiken Nedergaard
National Institutes of Health (U19NS128613)
- Maiken Nedergaard
Army Research Office (W911NF1910280)
- Maiken Nedergaard
Human Frontier Science Program (RGP0036)
- Maiken Nedergaard
Simons Foundation (811237)
- Maiken Nedergaard
Adelson Family Foundation
- Maiken Nedergaard
The views and conclusions contained in this article are solely those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the National Institutes of Health, the Army Research Office, or the U.S. Government. The U.S. Government is authorized to reproduce and distribute reprints for Government purposes notwithstanding any copyright notation herein. The funding agencies have taken no part on the design of the study, data collection, analysis, interpretation, or in writing of the manuscript.
Ethics
Animal experimentation: All experiments were performed based on approval received from both the Danish Animal Experiments Inspectorate (License number: 2020-15-0201-00581) and the University of Rochester Medical Center Committee on Animal Resources (UCAR, Protocol 2011-023).
Copyright
© 2023, Gomolka 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
-
- 3,322
- views
-
- 695
- downloads
-
- 58
- 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)
Loss of aquaporin-4 results in glymphatic system dysfunction via brain-wide interstitial fluid stagnation
eLife 12:e82232.
https://doi.org/10.7554/eLife.82232
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.
