59. Inflammation and Redox Dysregulation in the Developing Brain and Schizophrenia

Abstract

Overall Abstract: Hirofumi Morishita Mistimed developmental trajectories of brain plasticity upon inflammation and redox dysregulation Daniella Dwir: Matrix metalloproteinase inhibition prevents the adult excitatory-inhibitory imbalance induced by the reciprocal interaction between neuroinflammation and oxidative stress during development. Thomas Lanz: Transcriptomic alterations in psychiatric disease and rodent models: inflammatory and redox pathways. Clark Jeffries: Networks of blood analytes are collectively informative of risk of conversion to schizophrenia Inflammation and redox dysregulation have emerged as neurodevelopmental insults that may affect the growing brain, along pathways potentially leading to psychosis pathogenesis. Our panel highlights these key pathways using state of the art molecular techniques. It will emphasize the critical role of the interactions between oxidative stress and inflammation leading to cellular and gross structural brain anomalies during development in both human and animal models. (a) H Morishita will report on a novel computational assessment of 436 transcriptional signatures suggesting that inflammation in children and adolescents may have unexpected differential negative consequences on postnatal development by disrupting neuroplasticity during critical windows of development. (b) D Dwir will present new data on interactions between oxidative stress and inflammation involving MMP-9 activated RAGE shedding during brain development, leading to parvalbumin interneuron (PVI) impairment characteristic of schizophrenia pathology. This circular amplification of oxidative stress and inflammation might play an important role in the maintenance until adulthood of cellular deficits starting early in life. (c) T Lanz will show differential expression of genes involved in oxidative phosphorylation and redox homeostasis in several neurodevelopmental animal models (genetic manipulation and/or environmental insults), highlighting transcriptional alterations similar to those observed in schizophrenia. (d) C Jeffries will present a correlation network analysis of plasma analytes from the NAPLS cohort. Subgroups of analytes were highly interconnected in controls, converters to schizophrenia, and nonconverters; however, different analytes populated different networks. Distinguished in network differences were PAI-1, MMP9, TIMP1, and other analytes. These multilevel approaches combined together point to developmental inflammation and redox dysregulation as a common pathological process central to schizophrenia. The elucidation of their underlying mechanisms holds considerable promise for innovative treatment and prevention.