Integrative analysis of disease signatures shows inflammation disrupts juvenile experience-dependent cortical plasticity

ABSTRACT

Throughout childhood and adolescence, periods of heightened neuroplasticity are critical for the development of healthy brain function and behavior. Given the high prevalence of neurodevelopmental disorders such as autism, identifying disruptors of developmental plasticity represents an essential step for developing strategies for prevention and intervention. Applying a novel computational approach that systematically assessed connections between 436 transcriptional signatures of disease and multiple signatures of neuroplasticity, we identified inflammation as a common pathological process central to a diverse set of diseases predicted to dysregulate plasticity signatures. We tested the hypothesis that inflammation disrupts developmental cortical plasticity in vivo using the mouse ocular dominance model of experience-dependent plasticity in primary visual cortex. We found administration of systemic lipopolysaccharide suppressed plasticity during juvenile critical period with accompanying transcriptional changes in a particular set of molecular regulators within primary visual cortex. These findings suggest inflammation may have unrecognized adverse consequences on the postnatal developmental trajectory and indicates that treating inflammation may reduce the burden of neurodevelopmental disorders.

SIGNIFICANCE STATEMENT During childhood and adolescence, heightened neuroplasticity allows the brain to reorganize and adapt to its environment. Disruptions in these malleable phases can result in permanent neurodevelopmental disorders. To identify pathological mechanisms that disrupt developmental neuroplasticity, we applied a systematic computational screen of hundreds of diseases for their impact on neuroplasticity. We discovered that inflammation would putatively disrupt neuroplasticity and validated this hypothesis in an in vivo experimental mouse model of developmental cortical plasticity. This work suggests that inflammation during the childhood period could have unrecognized negative consequences on the neurodevelopmental trajectory.