Paradoxes in the Ontological Classification of Glia- Evidence for an Important New Class of Brain Cells with Primary Functions in Iron Regulation

The ontological categorization of the cellular elements of the brain was proposed over a century ago by Santiago Ramón y Cajal (neurons, astroglia) and Pío del Río-Hortega (oligodendroglia, microglia). It combines histochemical observations of morphology with allied inferences about the specialized functions and origins (ectoderm or mesoderm) of each cellular element. This ontology shapes modern neuroscience, with the main non-neuronal cells – astroglia, oligodendroglia and microglia – viewed as having distinct primary roles relating to metabolic support, myelination and protection of neurons, the information signaling cells. Yet contemporary techniques, ranging from electrophysiology to single-cell transcriptomics and ultrahigh resolution spectroscopy, are revealing intersecting molecular profiles and functional capacities of these cell groups, for example metabolic support, neuroimmune and signaling functions in oligodendroglia. Here we identify discrepancies in current glial paradigms from empirical, evolutionary and pragmatic perspectives. We suggest that a subset of cells often viewed as oligodendroglia instead have iron-related primary functions that are central to all aspects of brain activity, rather than myelin-related primary functions. We discuss implications for pathogenesis across the spectrum of neuropsychiatric and neurological disorders, including neurodegenerative conditions such as Alzheimer’s disease and other less common cognitive, movement and neurobehavioral disorders, stroke and cerebrovascular disease, glioblastoma and other brain cancers and neuroimmune conditions. We also briefly address the question of where these cells reside within existing glial compartments and lineages, implications for the ontological classification of other glial cells and research limitations that must be overcome going forward.