Fundamental disincorporation and early non-inflammatory microglia alterations: Possible bridging phenomena between neurobiology and psychopathology in schizophrenia

Increasing evidence shown that schizophrenia (SCZ) is associated with immunological aberrations. Particularly, microglia, the resident innate immune cells of the brain, have been implicated in SCZ pathogenesis. However, despite the abundance of empirical findings highlighting the role of microglia-mediated neuroinflammation in the neuropathology development in a wide range of central nervous system (CNS) disorders, non-inflammatory abnormalities in this cellular compartment have been associated with neuropsychiatric manifestation of SCZ in some postmortem works and in SCZ animal models. We hypothesize that at least some of these non-inflammatory perturbations represent the core neurobiological features of a “disincorporated” state of microglia in SCZ and indicate a switch from homeostatic coupling/functional response to maladaptive reaction to environmental inputs. This work aims to summarize experimental evidence that support this possible novel conceptual paradigm. This hypothesis needs further confirmations. In summary, the possible role of microglia in the pathogenesis of SCZ is certainly complex with conflicting evidence. Therefore, new conceptual paradigms useful for capturing the fundamental alterations of microglia seem to be required. Considering the need for experimental confirmation, the ecological idea of microglial disincorporation might be a first step in this direction, sufficiently supported by recent literature.