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
-
- 3,041
- views
-
- 635
- downloads
-
- 49
- 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
Sleep associated memory consolidation and reactivation play an important role in language acquisition and learning of new words. However, it is unclear to what extent properties of word learning difficulty impact sleep associated memory reactivation. To address this gap, we investigated in 22 young healthy adults the effectiveness of auditory targeted memory reactivation (TMR) during non-rapid eye movement sleep of artificial words with easy and difficult to learn phonotactical properties. Here, we found that TMR of the easy words improved their overnight memory performance, whereas TMR of the difficult words had no effect. By comparing EEG activities after TMR presentations, we found an increase in slow wave density independent of word difficulty, whereas the spindle-band power nested during the slow wave up-states – as an assumed underlying activity of memory reactivation – was significantly higher in the easy/effective compared to the difficult/ineffective condition. Our findings indicate that word learning difficulty by phonotactics impacts the effectiveness of TMR and further emphasize the critical role of prior encoding depth in sleep associated memory reactivation.
-
- Neuroscience
The neural mechanisms that willfully direct attention to specific locations in space are closely related to those for generating targeting eye movements (saccades). However, the degree to which the voluntary deployment of attention to a location necessarily activates a corresponding saccade plan remains unclear. One problem is that attention and saccades are both automatically driven by salient sensory events; another is that the underlying processes unfold within tens of milliseconds only. Here, we use an urgent task design to resolve the evolution of a visuomotor choice on a moment-by-moment basis while independently controlling the endogenous (goal-driven) and exogenous (salience-driven) contributions to performance. Human participants saw a peripheral cue and, depending on its color, either looked at it (prosaccade) or looked at a diametrically opposite, uninformative non-cue (antisaccade). By varying the luminance of the stimuli, the exogenous contributions could be cleanly dissociated from the endogenous process guiding the choice over time. According to the measured time courses, generating a correct antisaccade requires about 30 ms more processing time than generating a correct prosaccade based on the same perceptual signal. The results indicate that saccade plans elaborated during fixation are biased toward the location where attention is endogenously deployed, but the coupling is weak and can be willfully overridden very rapidly.
