59.1 Mistimed Developmental Trajectories of Brain Plasticity Upon Inflammation and Redox Dysregulation

摘要

>Background: Childhood and adolescent critical periods of heightened neuroplasticity are essential for development of normal brain function and behavior. Disruption of these periods of developmental plasticity may alter the neurodevelopmental trajectory and may confer risk for psychiatric and neurodevelopmental disorders. Identification of disruptors of developmental plasticity windows is essential for prevention and therapeutic intervention. >Methods: We developed and applied an integrative bioinformatics approach to systematically match plasticity to 436 disease signatures to yield a ranked list of diseases most likely to dysregulate plasticity signature genes. We applied a novel Disease Leverage Analysis across the ranked disease list to identify shared pathophysiology that may disrupt developmental plasticity. Informatics-driven hypothesis was then experimentally validated using the ocular dominance model of experience-dependent cortical plasticity. >Results: Through a novel computational assessment of transcriptional signatures of various diseases and multiple signatures of neuroplasticity, we found inflammation as a common pathological process central to a broad range of diseases predicted to dysregulate transcriptional signatures of plasticity. To experimentally test the hypothesis that inflammation would disrupt developmental plasticity in vivo, we used the ocular dominance model of experience-dependent cortical plasticity and found that systemic lipopolysaccharide suppresses postnatal cortical plasticity by accompanying transcriptome changes in a specific set of molecular regulators of plasticity. >Conclusion: Together with our previous study demonstrated that late adolescent redox dysregulation can lead to an open ended critical period for cortical plasticity (Morishita et al Biol Psychiatry 2015), our study suggests inflammation in children and adolescence may have unexpected differential negative consequences on the postnatal developmental trajectory than previously realized by disrupting neuroplasticity during critical windows of development. Mistimed developmental trajectories of brain plasticity may underlie, in part, the pathophysiology of schizoiphreania and other psychiatric disorders associated with inflammation.