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
Humberto Payne Mestre
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.
Reviewing Editor
- Saad Jbabdi, University of Oxford, United Kingdom
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).
Version history
- Received: July 28, 2022
- Preprint posted: July 29, 2022 (view preprint)
- Accepted: February 8, 2023
- Accepted Manuscript published: February 9, 2023 (version 1)
- Accepted Manuscript updated: February 9, 2023 (version 2)
- Version of Record published: March 8, 2023 (version 3)
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
-
- 2,488
- views
-
- 542
- downloads
-
- 21
- 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
-
- Genetics and Genomics
- Neuroscience
Genome-wide association studies have revealed >270 loci associated with schizophrenia risk, yet these genetic factors do not seem to be sufficient to fully explain the molecular determinants behind this psychiatric condition. Epigenetic marks such as post-translational histone modifications remain largely plastic during development and adulthood, allowing a dynamic impact of environmental factors, including antipsychotic medications, on access to genes and regulatory elements. However, few studies so far have profiled cell-specific genome-wide histone modifications in postmortem brain samples from schizophrenia subjects, or the effect of antipsychotic treatment on such epigenetic marks. Here, we conducted ChIP-seq analyses focusing on histone marks indicative of active enhancers (H3K27ac) and active promoters (H3K4me3), alongside RNA-seq, using frontal cortex samples from antipsychotic-free (AF) and antipsychotic-treated (AT) individuals with schizophrenia, as well as individually matched controls (n=58). Schizophrenia subjects exhibited thousands of neuronal and non-neuronal epigenetic differences at regions that included several susceptibility genetic loci, such as NRG1, DISC1, and DRD3. By analyzing the AF and AT cohorts separately, we identified schizophrenia-associated alterations in specific transcription factors, their regulatees, and epigenomic and transcriptomic features that were reversed by antipsychotic treatment; as well as those that represented a consequence of antipsychotic medication rather than a hallmark of schizophrenia in postmortem human brain samples. Notably, we also found that the effect of age on epigenomic landscapes was more pronounced in frontal cortex of AT-schizophrenics, as compared to AF-schizophrenics and controls. Together, these data provide important evidence of epigenetic alterations in the frontal cortex of individuals with schizophrenia, and remark for the first time on the impact of age and antipsychotic treatment on chromatin organization.
-
- Neuroscience
Combining information from multiple senses is essential to object recognition, core to the ability to learn concepts, make new inferences, and generalize across distinct entities. Yet how the mind combines sensory input into coherent crossmodal representations - the crossmodal binding problem - remains poorly understood. Here, we applied multi-echo fMRI across a four-day paradigm, in which participants learned 3-dimensional crossmodal representations created from well-characterized unimodal visual shape and sound features. Our novel paradigm decoupled the learned crossmodal object representations from their baseline unimodal shapes and sounds, thus allowing us to track the emergence of crossmodal object representations as they were learned by healthy adults. Critically, we found that two anterior temporal lobe structures - temporal pole and perirhinal cortex - differentiated learned from non-learned crossmodal objects, even when controlling for the unimodal features that composed those objects. These results provide evidence for integrated crossmodal object representations in the anterior temporal lobes that were different from the representations for the unimodal features. Furthermore, we found that perirhinal cortex representations were by default biased towards visual shape, but this initial visual bias was attenuated by crossmodal learning. Thus, crossmodal learning transformed perirhinal representations such that they were no longer predominantly grounded in the visual modality, which may be a mechanism by which object concepts gain their abstraction.
