Microglia sequelae: brain signature of innate immunity in schizophrenia

Schizophrenia is a psychiatric disorder with significant impact on individuals and society. The current pharmacologic treatment, which principally alleviates psychosis, is focused on neurotransmitters modulation, relying on drugs with severe side effects and ineffectiveness in a significant percentage of cases. Therefore, and due to difficulties inherent to diagnosis and treatment, it is vital to reassess alternative cellular and molecular drug targets. Distinct risk factors - genetic, developmental, epigenetic, and environmental - have been associated with disease onset and progression, giving rise to the proposal of different pathophysiological mechanisms and putative pharmacological targets. Immunity is involved and, particularly microglia - innate immune cells of the central nervous system, critically involved in brain development - have captured attention as cellular players. Microglia undergo marked morphologic and functional alterations in the human disease, as well as in animal models of schizophrenia, as reported in several original papers. We cluster the main findings of clinical studies by groups of patients: (1) at ultra-high risk of psychosis, (2) with a first episode of psychosis or recent-onset schizophrenia, and (3) with chronic schizophrenia; in translational studies, we highlight the time window of appearance of particular microglia alterations in the most well studied animal model in the field (maternal immune activation). The organization of clinical and translational findings based on schizophrenia-associated microglia changes in different phases of the disease course may help defining a temporal pattern of microglia changes and may drive the design of novel therapeutic strategies.