Neonatal testosterone voids sexually differentiated microglia morphology and behavior.

The involvement of immunity in psychiatric disorders, such as anxiety, is typified by the morphologic adaptation of microglia, immune cells of the brain, to anxiogenic stimuli. We previously reported sexually differentiated microglia morphology in adult rodents, in brain locations implicated in anxiety, including the pre-frontal cortex. These physiologic differences likely drive sex-dependent patterns of microglia morphologic remodeling in response to varied stress conditions in different periods of life, that correlate with sex-dependent behavioral adaptation to anxiogenic stimuli. The time-window of appearance of sex differences in microglia, correlating with sex-specific behavioral performance in anxiogenic conditions are still unknown. In rodents, a postnatal peak of the sexual hormone testosterone is determinant for the so-called brain masculinization and sex-determined behavioral traits. In the present work we aim to clarify if differences in microglia morphology are present at birth or can be driven by postnatal testosterone and impacts on the ability to deal with an anxiogenic context. Differences in microglia morphology are not present at birth, but are observable at adolescence (increased complexity of male microglia, particularly in branches more proximal to the soma), when differences in behavior are also observed. Our data also show that adolescent females neonatally treated with testosterone exhibit masculinized microglia and behavior. Importantly, between adolescence and adulthood, a sex-determined shift in the pattern of complexity takes place and microglia from females become more complex. When testosterone is administered, this morphological effect is partially abolished, approximating microglia and behavior to the male phenotype.

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.