Autism spectrum disorder (ASD) is a neurodevelopmental disorder affecting approximately 1 in 110 children in North America. Valproic acid (VPA) is a multi-target drug widely used to treat epilepsy. It is also a histone deacetylase inhibitor and fetal exposure to it increases the risk of ASD. One important hallmark of ASD is an unusually large brain size around the age of 2 years. The cause of this enlargement is not known, but it is speculated that a lack of pruning of dendrites may be associated with the large brains. The effect of prenatal exposure to VPA on microglial survival during postnatal brain development has not been studied and may provide some potential hints regarding the etiology of this disorder. In this study, we have tried to delineate the effect of VPA on macrophage/microglia activation states/survival both in vitro and in vivo to better understand VPA's underlying mechanism in this disorder.
Based on the experiments conducted, it was observed that VPA potentiated the response to endotoxin stimuli by increasing the production of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) from two separate macrophage cell lines. VPA was further evaluated using in vivo experiments and was shown that exposure during embryogenesis causes a reduction in the number of microglia in the primary motor cortex (PMC) at postnatal day 6 (P6) and postnatal day 10 (P10) in male mice. Similar reduction in microglial number was observed in female mice at P10. However, the effects of VPA were more pronounced in male mice than female mice. These data suggests that VPA alters the activation states of macrophage/microglia as well as affects the survival in early postnatal brain development. The effect of VPA on microglial survival/activation state may be partly responsible in mediating the unusual brain size observed in the pathology of ASD. In the future, pharmacological intervention aimed at protecting the macrophage/microglia population during crucial period of brain development may be beneficial in ASD.
|Advisor:||Carroll, Richard T.|
|Commitee:||Barnbaum, Deborah R., Caldwell, Heather, Dluzen, Dean, Van der Schyf, Cornelis J.|
|School:||Kent State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Keywords:||Autism, Cytokines, Macrophage, Microglia, Primary motor cortex, Valproic acid|
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