UCLA

Genetic and environmental factors are both likely to contribute to neurodevelopmental disorders, including autism spectrum disorders. In this study, we examined the combinatorial effect of two factors thought to be involved in autism - reduction in the expression of the extracellular matrix protein reelin and prenatal exposure to an organophosphate pesticide, chlorpyrifos oxon on mouse behavior and brain morphology. Mice with either reduced reelin expression or prenatal exposure to chlorpyrifos oxon exhibited subtle changes in ultrasound vocalization, open field behavior, social interaction, and repetitive behavior. Paradoxically, mice exposed to both variables often exhibited a mitigation of abnormal behaviors, rather than increased behavioral abnormalities as expected. We also identified specific differences in males and females in response to both of these variables. In addition to behavioral abnormalities, we identified anatomical alterations in cell positioning and organization in the olfactory bulb, piriform cortex, hippocampus, and cerebellum in adolescent mice. As with our behavioral studies, anatomical alterations also appeared to be ameliorated in the presence of both variables. Examination of adult brains showed that there are no obvious changes in cell position in the cortex, hippocampus, and cerebellum, and no loss of cellular subtypes. However, there were specific effects on dendritic spines in both the cortex and hippocampus, suggesting alterations in synaptic connectivity. Western blot analysis shows that prenatal exposure to chlorpyrifos oxon transiently increases reelin protein expression in mouse embryos, but that by adulthood, reelin protein levels are decreased, providing a possible biochemical explanation for our findings. While these observations support an interaction between reelin expression and CPO exposure, our results suggest a complexity to this interaction beyond an additive effect of individual phenotypes.