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.
Highlights
Solute transport through the extracellular space (ECS) in brain is of considerable importance for the delivery of nutrients and drugs to brain cells and for the clearance of metabolites, neurotransmitters and toxic macromolecules
All three dextrans were seen at the brain surface and in the paravascular spaces after fixation (Figure 1A), confirming that solutes applied to the CSF can circulate around the brain and enter the paravascular spaces
Analysis of the fluorescence intensity of each dextran as a function of distance from the brain surface, where tracer is thought to accumulate in a sub-pial space that is contiguous with the paravascular space (Hladky and Barrand, 2014), demonstrated that transport into the brain was strongly size-dependent (Figure 1B)
Summary
Solute transport through the extracellular space (ECS) in brain is of considerable importance for the delivery of nutrients and drugs to brain cells and for the clearance of metabolites, neurotransmitters and toxic macromolecules. Nedergaard and colleagues (Iliff et al, 2012; Jessen et al, 2015) have proposed that convective, ‘glymphatic’ flow of cerebrospinal fluid though the ECS from the para-arterial to the para-venous spaces is largely responsible for solute transport in parenchymal ECS. Glymphatic transport was proposed to have broad consequences in normal brain physiology and in the diseased brain, including clearance of b-amyloid in neurodegenerative disease (Iliff et al, 2012) and metabolic waste products during sleep (Xie et al, 2013), and removal of excess fluid in various forms of brain edema (Thrane et al, 2014). It was further proposed that AQP4, a water channel expressed
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