Test of the 'glymphatic' hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma

• Published in: eLife 2017-08, Vol.6
• Main Authors: Smith, Alex J, Yao, Xiaoming, Dix, James A, Jin, Byung-Ju, Verkman, Alan S
• Format: Article
• Language: English
• Subjects: Animals; Aquaporin 4; Aquaporin 4 - deficiency; Aquaporin 4 - genetics; Aquaporins; Arachnoid; Biological Transport; Brain; Carbocyanines - chemistry; Carbocyanines - metabolism; Convection; CSF; Dextran; Dextrans; Dextrans - chemistry; Dextrans - metabolism; Diffusion; extracellular space; Fluoresceins - metabolism; Fluorescence; Fluorescence Recovery After Photobleaching; Fluorescent Dyes - chemistry; Fluorescent Dyes - metabolism; Gene deletion; Gene Expression; Genes; glymphatic hypothesis; Heart Arrest; Injections, Intraventricular; Mice; Mice, Knockout; Models, Biological; Neuroscience; Parenchyma; Parenchymal Tissue - metabolism; Parenchymal Tissue - ultrastructure; Photobleaching; Physiology; Polysaccharides; Rats; Solute movement; Solutes; Standard deviation; Statistical analysis; Subarachnoid Space - metabolism; Subarachnoid Space - ultrastructure
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.27679

Transport of solutes through brain involves diffusion and convection. The importance of convective flow in the subarachnoid and paravascular spaces has long been recognized; a recently proposed 'glymphatic' clearance mechanism additionally suggests that aquaporin-4 (AQP4) water channels facilitate convective transport through brain parenchyma. Here, the major experimental underpinnings of the glymphatic mechanism were re-examined by measurements of solute movement in mouse brain following intracisternal or intraparenchymal solute injection. We found that: (i) transport of fluorescent dextrans in brain parenchyma depended on dextran size in a manner consistent with diffusive rather than convective transport; (ii) transport of dextrans in the parenchymal extracellular space, measured by 2-photon fluorescence recovery after photobleaching, was not affected just after cardiorespiratory arrest; and (iii) gene deletion did not impair transport of fluorescent solutes from sub-arachnoid space to brain in mice or rats. Our results do not support the proposed glymphatic mechanism of convective solute transport in brain parenchyma.