Invertebrate glial barriers as a model for understanding blood-brain barrier evolution.

Biological barriers play a crucial role in maintaining tissue homeostasis across diverse animal taxa, from invertebrates to mammals. In the nervous system, they regulate ion balance, metabolic exchange, and immune protection, ensuring proper neuronal function. In arthropods, the blood-brain barrier (BBB) is primarily formed by the perineurium, consisting of perineurial and subperineurial glial cells that establish septate junctions to restrict diffusion. Cephalopods, such as octopuses and squids, possess two distinct BBBs: one formed by glial cells and another by pericytes, depending on the type of brain blood vessel. Similarly, in vertebrates such as sharks, skate, rays, and sturgeons, the BB is also formed by glial cells. In contrast, the BBBs of most vertebrates rely on endothelial tight junctions, although astrocytes and pericytes contribute significantly to BBB maintenance and function. Importantly, glial barriers also exist in vertebrates, including the blood-nerve barrier (BNB), and the blood-cerebrospinal fluid barrier (BCSFB). Despite structural differences, the molecular mechanisms governing barrier formation, function, and plasticity show remarkable evolutionary conservation between invertebrates and vertebrates. In this review, we examine the diversity of glial barriers, their structural and functional parallels, evolutionary origins, and the key molecular pathways that regulate their development.