Aquaporin 4 and glymphatic flow have central roles in brain fluid homeostasis

In their recent Review (MacAulay, N. Molecular mechanisms of brain water transport. Nat. Rev. Neurosci. 22, 326–344 (2021))1, MacAulay highlights many open questions about how brain water transport is controlled. They posit that cotransport of water may bridge the gap in our understanding of cellular and barrier brain water transport. As the existence of the glymphatic system and its dependence upon the glial water channel aquaporin 4 (AQP4) have been controversial, MacAulay places them outside the scope of their Review. We agree that a lack of mechanistic insight into them represents a significant gap in current knowledge of the brain in health and disease. However, it is necessary to contextualize the role of AQP4 in glymphatic function (which we think deserves more attention) and address the need for tighter definitions when describing the fluids involved. As MacAulay’s review has such a broad title, our aim is to provide its reader with an appreciation of these important and, in some cases, emerging concepts in brain fluid dynamics.