Both genetic perturbations and prenatal environmental insults are important risk factors for the development of autism spectrum disorder (ASD) in offspring. However, little is known about how these two components interact at the cellular level to influence brain development and function. Interestingly, recent epidemiological studies have shown that maternal diabetes is associated with an increased risk of developing ASD in offspring. In gestational diabetes, hyperglycemia triggers an elevated production of methylglyoxal, which in turn results in the modification and disruption of cellular proteins. This metabolite is normally detoxified by the enzyme glyoxalase 1 (Glo1). Importantly, Glo1 polymorphisms have recently been linked to ASD. How then might this MG-Glo1 pathway regulate neural development? I will test the hypothesis that deregulation of the Glo1-MG pathway caused by maternal environmental insults (MG elevation) and genetic perturbations (Glo1 deficiency) might impact brain development by deregulating embryonic neural precursor cells (NPCs) and adult neural stem cells in offspring. I have shown that elevated MG or Glo1 knockdown depletes NPCs as a result of premature neurogenesis in the developing mouse cortex. Building on this preliminary data, I will test whether this early disruption of embryonic NPCs leads to a long-term decrease of adult neural stem cells (NSCs) that are known to be important for cognition. I will then characterize these mice behaviorally with our collaborators. Particularly, I will examine behaviors relevant to ASD such as response to social novelty. This work will provide mechanistic insight into how the maternal environment might mediate long-term effects on human biology and health.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
