FIGURE 6.

Phylogenetic development of the glymphatic system. When the nervous system evolved from diffuse neural networks to form centralized ganglia, the first supporting neuroglial cells also appeared. Thus, all bilateria have neuroglia. Ventricles developed at a phylogenetic stage when the nervous system progressed from being a plate-like structure to form a neural tube with a lumen containing cerebral spinal fluid (CSF), which is a feature of all chordates. In vertebrate evolution, brains might have grown so large that the tissue could not be nourished by diffusion from a vascular surface plexus, thus requiring the development of intrinsic brain vascularization. The subarachnoid space covering the external surface of the brain with CSF is seemingly present in all terrestrial vertebrates, such that extensions of the subarachnoid space into the brain parenchyma (i.e., the perivascular spaces) are likely also to be present in amphibians, reptiles, birds, and mammals. The evolutionary innovation of a perivascular endfeet layer of protoplasmic astrocytes with expression of aquaporin 4 (AQP4) polarized toward the blood vessel seems to be a feature of mammalian and avian brains. Thus, since the glymphatic pathway appears fully developed in mammals and birds, we surmise that it must also have been present in their common ancestor, before the divergence of sauropsids (ancestors of reptiles and avians) and synapsids (ancestors of mammals). CNS, central nervous system; SAS, subarachnoid space.