The Mechanism of Downregulated Interstitial Fluid Drainage Following Neuronal Excitation

Abstract

The drainage of brain interstitial fluid (ISF) has been observed to slow down following neuronal excitation, although the mechanism underlying this phenomenon is yet to be elucidated. In searching for the changes in the brain extracellular space (ECS) induced by electrical pain stimuli in the rat thalamus, significantly decreased effective diffusion coefficient (DECS) and volume fraction (α) of the brain ECS were shown, accompanied by the slowdown of ISF drainage. The morphological basis for structural changes in the brain ECS was local spatial deformation of astrocyte foot processes following neuronal excitation. We further studied aquaporin-4 gene (APQ4) knockout rats in which the changes of the brain ECS structure were reversed and found that the slowed DECS and ISF drainage persisted, confirming that the down-regulation of ISF drainage following neuronal excitation was mainly attributable to the release of neurotransmitters rather than to structural changes of the brain ECS. Meanwhile, the dynamic changes in the DECS were synchronized with the release and elimination processes of neurotransmitters following neuronal excitation. In conclusion, the downregulation of ISF drainage following neuronal excitation was found to be caused by the restricted diffusion in the brain ECS, and DECS mapping may be used to track the neuronal activity in the deep brain.

The Alteration of Brain Interstitial Fluid Drainage with Myelination Development

“…Significantly disturbed ISF drainage has been observed in a demyelinated rat model caused by chemical toxicity [ 6 ]. A recent study by Li et al demonstrated downregulated ISF drainage following neuronal excitation [ 13 ]. The study showed that the reduced ISF drainage was caused by the slow diffusion in ECS and the release of excitatory neurotransmitters, including glutamate, glutamine, N-acetylaspartate, and aspartate [ 13 ].…”

“…A recent study by Li et al demonstrated downregulated ISF drainage following neuronal excitation [ 13 ]. The study showed that the reduced ISF drainage was caused by the slow diffusion in ECS and the release of excitatory neurotransmitters, including glutamate, glutamine, N-acetylaspartate, and aspartate [ 13 ]. Under different anesthesia, the release of noradrenaline (NA) in the brain ECS could also determine the drainage rate of ISF [ 29 ].…”

“…The Gd-DTPA tracer (Magnevist; Bayer Schering Pharma AG, Berlin, Germany) and the optic-magnetic bimodal molecular tracer Gd-DO3A-ethylthiouret-fluorescein (Gd-DO3A-EA-FITC; synthesized by our lab) were diluted to 10 mmol/L [ 6 , 13 , 14 ]. The tracers were delivered for 10 min with an automated drug administration system (Harvard Apparatus, Holliston, MA, USA).…”

“…Electron microscopy was performed using a Nikon2000 transmission electron microscope [ 6 , 13 , 15 ]. The thickness of the myelin sheath (MSTH) and maturity of myelin in the Cn and internal capsule were measured.…”

Cerebral Microcirculation, Perivascular Unit, and Glymphatic System: Role of Aquaporin-4 as the Gatekeeper for Water Homeostasis

“…Is the activity of AQP4 channels somehow responsible for this inversed relationship between neurovascular coupling and glymphatic flow? Indeed, the trend to the physiological flow reduction in regions of neuronal activation was reversed in AQP4 knockouts ( 171 ). AQP4 expression and polarization are also strongly dependent on circadian rhythm ( 162 , 172 ), suggesting that proper AQP4 activity is required for physiological glymphatic stagnancy in periods/areas of neuronal excitation.…”