Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that affects approximately 1 in 1,000 children in the US, but the exact cause is not known. Inflammation early in life, either in utero or postnatally, is a major rik factor for development of disorders of mental health, including ASD. The cerebellum is a brain region that shows consistent pathologies in individuals with ASD. To-date, there has been little consideration of the impact of inflammation on cerebellar development. The broad goal of this proposal is to elucidate the neural mechanisms underlying a sensitive period in postnatal cerebellar development, in order to understand how this particular period may contribute to an increased risk for ASD from environmental insult. Prostaglandins are associated with proinflammatory signaling in the brain in response to injury or infection, however they also appear to play a key role in normal Purkinje cell dendritic development in the cerebellum. Our laboratory has established that normal Purkinje cell development is regulated by a prostaglandin E2 - estradiol signaling pathway which, if thrown out of balance, results in abnormal Purkinje cell dendritic development as well as abnormal social interactions and pain sensitivity characteristic of ASD. We propose to investigate the role of this prostaglandin E2 - estradiol pathway in creating a sensitive period for Purkinje cell development, and how its disruption affects normal behavior.
Three specific aims will test several hypotheses by determining 1) the expression patterns of key components of the prostaglandin E2 - estradiol pathway, 2) which components are necessary for creating the sensitive period, and 3) how changes in this pathway result in behavioral deficits relevant to ASD. These experiments will give insight into normal cerebellar development and possible environmental risk factors for development of ASD, and could shape the effort for its prevention.
The multiple variables contributing to the risk for developing autism spectrum disorder (ASD) have not been fully characterized, and there is mounting interest in the role of early fever and inflammation in the development of this prevalent disorder. ASD is a neurodevelopmental disorder, and therefore likely to include sensitive periods of heightened vulnerability. Studying the basic mechanisms through which developmental sensitive periods in the brain are established and how perturbations during these periods increase risk for behavioral deficits related to ASD will provide insight into how to avoid or counteract current environmental factors that may increase a child's risk of developing ASD.
|Hoffman, Jessica F; Wright, Christopher L; McCarthy, Margaret M (2016) A Critical Period in Purkinje Cell Development Is Mediated by Local Estradiol Synthesis, Disrupted by Inflammation, and Has Enduring Consequences Only for Males. J Neurosci 36:10039-49|