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    Evidence that inflammation promotes estradiol synthesis in human cerebellum during early childhood

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    Author
    Wright, C.L.
    Hoffman, J.H.
    McCarthy, M.M.
    Date
    2019
    Journal
    Translational Psychiatry
    Publisher
    Springer Nature Publishing
    Type
    Article
    
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    See at
    https://dx.doi.org/10.1038/s41398-018-0363-8
    Abstract
    Discovering and characterizing critical and sensitive periods in brain development is essential for unraveling the myriad variables that impact disease risk. In previous work, we identified a critical period in cerebellar development in the rat that depends upon an intrinsic gene expression program and links increased prostaglandin production to local estradiol synthesis by stimulating Cyp19a, the estradiol synthetic enzyme, aromatase. This intrinsic critical period is sensitive to disruption by either inflammation or administration of cyclooxygenase (COX) inhibitors, ultimately impacting Purkinje cell dendritic growth. In a first step towards determining if a similar sensitive period exists in humans, the same gene expression profile was characterized in post-mortem cerebellar tissue of 58 children aged 0 to 9 years. Subjects were categorized as experiencing inflammation or not at the time of death. In individuals experiencing inflammation and over 1 year of age, there was a significant increase in the messenger RNA (mRNA) of the COX-1 and COX-2 enzymes and this strongly correlated with mRNA levels of aromatase. A step-wise linear model accounted for 94% of the variance in aromatase mRNA levels by co-variance with the COX enzymes, prostaglandin E2 synthase and other inflammatory mediators (Toll-like receptor 4), and Purkinje cell markers (calbindin, estrogen receptor 2). The influence of inflammation on these measures was not seen in subjects younger than 1 year. These data suggest a sensitive period to inflammation in the human cerebellum begins at about 1 year of age and may provide insight into sources of vulnerability of very young children to either inflammation or drugs designed to treat it. © 2019, The Author(s).
    Sponsors
    This work was supported by NIH R01MH091424 to MMM. Tissue was obtained from the University of Maryland Brain and Tissue Bank.
    Keyword
    Cerebellum--growth & development
    Inflammation
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85060929404&doi=10.1038%2fs41398-018-0363-8&partnerID=40&md5=6f5ca2f779099c5c4cb8393342528f0e; http://hdl.handle.net/10713/8542
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41398-018-0363-8
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