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Application of fluorescent dextrans to the brain surface under constant pressure reveals AQP4-independent solute uptake

Extracellular solutes in the central nervous system are exchanged between the interstitial fluid, the perivascular compartment, and the cerebrospinal fluid (CSF). The “glymphatic” mechanism proposes that the astrocyte water channel aquaporin-4 (AQP4) is a major determinant of solute transport betwee...

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Autores principales: Smith, Alex J., Akdemir, Gokhan, Wadhwa, Meetu, Song, Dan, Verkman, Alan S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210582/
https://www.ncbi.nlm.nih.gov/pubmed/34128962
http://dx.doi.org/10.1085/jgp.202112898
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author Smith, Alex J.
Akdemir, Gokhan
Wadhwa, Meetu
Song, Dan
Verkman, Alan S.
author_facet Smith, Alex J.
Akdemir, Gokhan
Wadhwa, Meetu
Song, Dan
Verkman, Alan S.
author_sort Smith, Alex J.
collection PubMed
description Extracellular solutes in the central nervous system are exchanged between the interstitial fluid, the perivascular compartment, and the cerebrospinal fluid (CSF). The “glymphatic” mechanism proposes that the astrocyte water channel aquaporin-4 (AQP4) is a major determinant of solute transport between the CSF and the interstitial space; however, this is controversial in part because of wide variance in experimental data on interstitial uptake of cisternally injected solutes. Here, we investigated the determinants of solute uptake in brain parenchyma following cisternal injection and reexamined the role of AQP4 using a novel constant-pressure method. In mice, increased cisternal injection rate, which modestly increased intracranial pressure, remarkably increased solute dispersion in the subarachnoid space and uptake in the cortical perivascular compartment. To investigate the role of AQP4 in the absence of confounding variations in pressure and CSF solute concentration over time and space, solutes were applied directly onto the brain surface after durotomy under constant external pressure. Pressure elevation increased solute penetration into the perivascular compartment but had little effect on parenchymal solute uptake. Solute penetration and uptake did not differ significantly between wild-type and AQP4 knockout mice. Our results offer an explanation for the variability in cisternal injection studies and indicate AQP4-independent solute transfer from the CSF to the interstitial space in mouse brain.
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spelling pubmed-82105822022-02-02 Application of fluorescent dextrans to the brain surface under constant pressure reveals AQP4-independent solute uptake Smith, Alex J. Akdemir, Gokhan Wadhwa, Meetu Song, Dan Verkman, Alan S. J Gen Physiol Article Extracellular solutes in the central nervous system are exchanged between the interstitial fluid, the perivascular compartment, and the cerebrospinal fluid (CSF). The “glymphatic” mechanism proposes that the astrocyte water channel aquaporin-4 (AQP4) is a major determinant of solute transport between the CSF and the interstitial space; however, this is controversial in part because of wide variance in experimental data on interstitial uptake of cisternally injected solutes. Here, we investigated the determinants of solute uptake in brain parenchyma following cisternal injection and reexamined the role of AQP4 using a novel constant-pressure method. In mice, increased cisternal injection rate, which modestly increased intracranial pressure, remarkably increased solute dispersion in the subarachnoid space and uptake in the cortical perivascular compartment. To investigate the role of AQP4 in the absence of confounding variations in pressure and CSF solute concentration over time and space, solutes were applied directly onto the brain surface after durotomy under constant external pressure. Pressure elevation increased solute penetration into the perivascular compartment but had little effect on parenchymal solute uptake. Solute penetration and uptake did not differ significantly between wild-type and AQP4 knockout mice. Our results offer an explanation for the variability in cisternal injection studies and indicate AQP4-independent solute transfer from the CSF to the interstitial space in mouse brain. Rockefeller University Press 2021-06-15 /pmc/articles/PMC8210582/ /pubmed/34128962 http://dx.doi.org/10.1085/jgp.202112898 Text en © 2021 Smith et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Smith, Alex J.
Akdemir, Gokhan
Wadhwa, Meetu
Song, Dan
Verkman, Alan S.
Application of fluorescent dextrans to the brain surface under constant pressure reveals AQP4-independent solute uptake
title Application of fluorescent dextrans to the brain surface under constant pressure reveals AQP4-independent solute uptake
title_full Application of fluorescent dextrans to the brain surface under constant pressure reveals AQP4-independent solute uptake
title_fullStr Application of fluorescent dextrans to the brain surface under constant pressure reveals AQP4-independent solute uptake
title_full_unstemmed Application of fluorescent dextrans to the brain surface under constant pressure reveals AQP4-independent solute uptake
title_short Application of fluorescent dextrans to the brain surface under constant pressure reveals AQP4-independent solute uptake
title_sort application of fluorescent dextrans to the brain surface under constant pressure reveals aqp4-independent solute uptake
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210582/
https://www.ncbi.nlm.nih.gov/pubmed/34128962
http://dx.doi.org/10.1085/jgp.202112898
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