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.
Highlights
The cerebellum is one of the first brain structures to emerge and one of the last to fully mature, at least in part because of its reciprocal closed-loop circuitry with multiple cortical regions[1]
ESR2 (ER-β), PTGER3 (EP3), and Toll-like receptor 4 (TLR4)-v1 and TLR4-v3 messenger RNA (mRNA) levels co-varied with postmortem interval (PMI), but PMI did not vary across sex, age, or inflammation at any level by three-way ANOVA
time tissue remained frozen (TTRF) was greater for individuals younger than 1 year and for samples from females, yet TTRF and pH did not co-vary with expression of any genes
Summary
The cerebellum is one of the first brain structures to emerge and one of the last to fully mature, at least in part because of its reciprocal closed-loop circuitry with multiple cortical regions[1]. The cerebellum is characterized by its role in intrinsic motor learning[2,3], but is gaining increasing appreciation for its role early in life to shape and refine neocortical circuits for affect and cognition[4]. Damage to the cerebellum in infancy is one risk factor among many contributing to whether a child is diagnosed with autism spectrum disorder (ASD), and is associated with perseverative behaviors and inability to perceive or match another’s emotions[8,9,10]. Pathologies of the cerebellum are strongly associated with schizophrenia[4,11], which is increasingly being viewed as a disorder with origins in development[12,13,14,15,16]
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