Maternal valproic acid exposure leads to neurogenesis defects and autism-like behaviors in non-human primates.
Hui ZhaoQiqi WangTing YanYu ZhangHui-Juan XuHao-Peng YuZhuchi TuXiangyu GuoYong-Hui JiangXiao-Jiang LiHuihui ZhouYong Q ZhangPublished in: Translational psychiatry (2019)
Despite the substantial progress made in identifying genetic defects in autism spectrum disorder (ASD), the etiology for majority of ASD individuals remains elusive. Maternal exposure to valproic acid (VPA), a commonly prescribed antiepileptic drug during pregnancy in human, has long been considered a risk factor to contribute to ASD susceptibility in offspring from epidemiological studies in humans. The similar exposures in murine models have provided tentative evidence to support the finding from human epidemiology. However, the apparent difference between rodent and human poses a significant challenge to extrapolate the findings from rodent models to humans. Here we report for the first time the neurodevelopmental and behavioral outcomes of maternal VPA exposure in non-human primates. Monkey offspring from the early maternal VPA exposure have significantly reduced NeuN-positive mature neurons in prefrontal cortex (PFC) and cerebellum and the Ki67-positive proliferating neuronal precursors in the cerebellar external granular layer, but increased GFAP-positive astrocytes in PFC. Transcriptome analyses revealed that maternal VPA exposure disrupted the expression of genes associated with neurodevelopment in embryonic brain in offspring. VPA-exposed juvenile offspring have variable presentations of impaired social interaction, pronounced stereotypies, and more attention on nonsocial stimuli by eye tracking analysis. Our findings in non-human primates provide the best evidence so far to support causal link between maternal VPA exposure and neurodevelopmental defects and ASD susceptibility in humans.
Keyphrases
- autism spectrum disorder
- endothelial cells
- induced pluripotent stem cells
- intellectual disability
- attention deficit hyperactivity disorder
- high fat diet
- pluripotent stem cells
- healthcare
- pregnancy outcomes
- birth weight
- spinal cord
- type diabetes
- emergency department
- pregnant women
- risk factors
- single cell
- brain injury
- spinal cord injury
- white matter
- skeletal muscle
- multiple sclerosis
- subarachnoid hemorrhage
- rna seq
- glycemic control
- contrast enhanced