Shedding Light on the Dark Side of the Microglia

Microglia, the resident immune cells of the central nervous system, are not a homogeneous population; their morphology, molecular profile, and even their ultrastructure greatly vary from one cell to another. Recent advances in the field of neuroimmunology have helped to demystify the enigma that currently surrounds microglial heterogeneity. Indeed, numerous microglial subtypes have been discovered such as the disease-associated microglia, neurodegenerative phenotype, and Cd11c-positive developmental population. Another subtype is the dark microglia (DM), a population defined by its ultrastructural changes associated with cellular stress. Since their first characterization using transmission electron microscopy, they have been identified in numerous disease conditions, from mouse models of Alzheimer's disease, schizophrenia, fractalkine signaling deficiency to chronic stress, just to name a few. A recent study also identified the presence of cells with a similar ultrastructure to the DM in postmortem brain samples from schizophrenic patients, underlining the importance of understanding the function of these cells. In this minireview, we aim to summarize the current knowledge on the DM, from their initial ultrastructural characterization to their documentation in various pathological contexts across multiple species. We will also highlight the current limitations surrounding the study of these cells and the future that awaits the DM.