Abstract
Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K+, Ca2+, and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or ‘glymphatic’ system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediated convective transport of fluid and solutes through the brain extracellular space (ECS) involving the aquaporin-4 (AQP4) water channel, and finally delivery of fluid to venules for clearance along peri-venous spaces. However, recent evidence favours important amendments to the ‘glymphatic’ hypothesis, particularly concerning the role of glia and transfer of solutes within the ECS. This review discusses studies which question the role of AQP4 in ISF flow and the lack of evidence for its ability to transport solutes; summarizes attributes of brain ECS that strongly favour the diffusion of small and large molecules without ISF flow; discusses work on hydraulic conductivity and the nature of the extracellular matrix which may impede fluid movement; and reconsiders the roles of the perivascular space (PVS) in CSF–ISF exchange and drainage. We also consider the extent to which CSF–ISF exchange is possible and desirable, the impact of neuropathology on fluid drainage, and why using CSF as a proxy measure of brain components or drug delivery is problematic. We propose that new work and key historical studies both support the concept of a perivascular fluid system, whereby CSF enters the brain via PVS convective flow or dispersion along larger caliber arteries/arterioles, diffusion predominantly regulates CSF/ISF exchange at the level of the neurovascular unit associated with CNS microvessels, and, finally, a mixture of CSF/ISF/waste products is normally cleared along the PVS of venules/veins as well as other pathways; such a system may or may not constitute a true ‘circulation’, but, at the least, suggests a comprehensive re-evaluation of the previously proposed ‘glymphatic’ concepts in favour of a new system better taking into account basic cerebrovascular physiology and fluid transport considerations.
Highlights
The brain is the most important regulatory site in the body, coordinating the input from sensory endings in all organs and the appropriate motor output in response, taking into account learning and memory, and allowing for running repairs to maintain active function
To return to the question—does the ‘glymphatic’ system exist, in the form of AQP4-dependent convective flow pathways bathing neurons, synapses and glia in the parenchyma? It is becoming increasingly apparent that under normal conditions, such flows likely do not exist in the neuropil of the gray matter
Rather than a ‘glymphatic’ system as originally proposed [91, 124, 125], the weight of the evidence suggests the existence of a perivascular fluid system for the CNS, with convective flow or dispersion along the perivascular spaces of larger vessels and diffusion predominantly regulating cerebrospinal fluid (CSF)/interstitial fluid (ISF) exchange at the level of the neurovascular unit associated with CNS microvessels, as proposed by several groups [6, 74, 80, 96, 137, 161, 162, 192]
Summary
The brain is the most important regulatory site in the body, coordinating the input from sensory endings in all organs and the appropriate motor output in response, taking into account learning and memory, and allowing for running repairs to maintain active function. The neurons responsible for this coordination and their synaptic interconnections use transmembrane ionic gradients and movements to generate essential potential changes, including action potentials that propagate along axons, and synaptic potentials generated in post-synaptic membranes by transmitters released from the presynaptic neuron. Homeostasis of the neural microenvironment depends on the effective separation of this environment from the blood while allowing efficient exchange of essential gases, nutrients and waste products of metabolism, and efficient removal of larger waste products and cell debris. The modern mammalian brain achieves all of these by compartmentalisation that allows dynamic exchange across key interfaces
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