Our brains consist of 80% water, which is continuously shifted between different compartments and cell types during physiological and pathophysiological processes. Disturbances in brain water homeostasis occur with pathologies such as brain oedema and hydrocephalus, in which fluid accumulation leads to elevated intracranial pressure. Targeted pharmacological treatments do not exist for these conditions owing to our incomplete understanding of the molecular mechanisms governing brain water transport. Historically, the transmembrane movement of brain water was assumed to occur as passive movement of water along the osmotic gradient, greatly accelerated by water channels termed aquaporins. Although aquaporins govern the majority of fluid handling in the kidney, they do not suffice to explain the overall brain water movement: either they are not present in the membranes across which water flows or they appear not to be required for the observed flow of water. Notably, brain fluid can be secreted against an osmotic gradient, suggesting that conventional osmotic water flow may not describe all transmembrane fluid transport in the brain. The cotransport of water is an unconventional molecular mechanism that is introduced in this Review as a missing link to bridge the gap in our understanding of cellular and barrier brain water transport.
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I would like to thank all the many great researchers, especially my mentor T. Zeuthen, with whom I have had the pleasure to discuss these topics with at length for the past few decades. I have learned so much from many of you! In addition, I would like to express my gratitude to my research team, past and present, for joining me on our quest to reach an understanding on how water crosses cell membranes in the brain. The work included in this Review was generously funded by the Lundbeck Foundation, the Independent Research Fund Denmark, the Novo Nordic Foundation, Thorberg’s Foundation, the Carlsberg Foundation, Friis’ Foundation, Danielsen’s Foundation, and the Hartmann Foundation.
The author declares no competing interests.
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- Dendritic beading
The bead-shaped swelling of dendrites during spreading depolarization.
- Blood–brain barrier
(BBB). The tight junction-coupled endothelial cell layer that separates the circulating blood from the brain tissue.
- Blood–CSF barrier
(BCSFB). The epithelial cell layer that separates the circulating blood from the cerebrospinal fluid (CSF)-filled ventricles.
- Osmotic water permeability
The ease with which water crosses a cell membrane with a given transmembrane osmotic challenge.
- Passive water transport
Water transport following the osmotic gradient.
- Active water transport
Water transport taking place independently of — or even against — a transmembrane osmotic gradient.
- Choroid plexus
The epithelial structures placed in the brain ventricles that secrete the majority of the CSF.
- Activity-evoked extracellular space shrinkage
The cellular (glial) swelling taking place during neuronal activity, monitored as the size of the extracellular space.
- Cotransport of water
The ability of cotransporters to translocate a fixed amount of water molecules in the direction of their transported solutes.
- Elevated intracranial pressure
With brain fluid accumulation in pathology, the intracranial pressure increases due to the confinements of the brain within the skull; this condition can be life threatening.
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MacAulay, N. Molecular mechanisms of brain water transport. Nat Rev Neurosci (2021). https://doi.org/10.1038/s41583-021-00454-8