Early life behavioral deficits and microglia remodeling in the mesocorticolimbic system precede the emergence of Schizophrenia-like symptoms.

Abstract

Microglia-mediated sensing, during development, dictates synapse formation/elimination and function. This depends on microglia morphology, in the sense their cellular processes adopt variable length/degree of ramification, in response to neuronal cues, in turn regulated by local microenvironmental conditions. In schizophrenia, two neuronal pathways of the mesocorticolimbic system are oppositely dysregulated, resulting in hypo- and hyper-dopaminergic tonus in target regions, prefrontal cortex (PFC) and nucleus accumbens (NAc). This bimodal tonus is associated with disease manifestations, including social symptoms. Although schizophrenia is a developmental disease, electrophysiological and behavioral preclinical data have been mainly obtained in adulthood and information about disease trajectory until adolescence (an important period of diagnosis) is very limited. The main goal of the present work is to characterize the morphological differentiation of microglia in PFC and NAc, in infancy and adolescence, using an experimental model of schizophrenia (rats prenatally exposed to methylazoxymethanol acetate, MAM) and to detect early manifestations of neurodevelopmental deficits. In infancy, MAM affects neurodevelopmental milestones and induces microglia hypertrophy in PFC and NAc, in both sexes. In adolescence, social behavior is affected (with subtle differences between sexes) and, notably, a region-specific microglia remodeling is observed: in PFC, there is a recovery of the physiological morphology, but an atrophic phenotype emerges in NAc. Although out of the scope of this work, in an attempt to validate the model in adult females, we screened for sex differences in behavior and (electro)physiology, aspects also discussed. This topic deserves a cautious analysis by the scientific community and reinforces the importance of performing preclinical studies in both sexes.