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

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.