Test of the 'Glymphatic' Hypothesis Demonstrates Diffusive and aquaporin-4-independent Solute Transport in Rodent Brain Parenchyma

Elife. 2017 Aug 21;6:e27679. doi: 10.7554/eLife.27679.

Abstract

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) Aqp4 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.

Keywords: CSF; aquaporin 4; convection; diffusion; extracellular space; glymphatic hypothesis; mouse; neuroscience; rat.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 4 / deficiency
  • Aquaporin 4 / genetics*
  • Biological Transport
  • Carbocyanines / chemistry
  • Carbocyanines / metabolism
  • Dextrans / chemistry
  • Dextrans / metabolism*
  • Diffusion
  • Fluoresceins / metabolism
  • Fluorescence Recovery After Photobleaching
  • Fluorescent Dyes / chemistry
  • Fluorescent Dyes / metabolism*
  • Gene Expression
  • Heart Arrest
  • Injections, Intraventricular
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Parenchymal Tissue / metabolism*
  • Parenchymal Tissue / ultrastructure
  • Rats
  • Subarachnoid Space / metabolism*
  • Subarachnoid Space / ultrastructure

Substances

  • Alexa Fluor 647
  • Aqp4 protein, mouse
  • Aquaporin 4
  • Carbocyanines
  • Dextrans
  • Fluoresceins
  • Fluorescent Dyes
  • fluorescein-dextran