Cellular and molecular mechanisms of BPA-induced disruption of neurodevelopment

About This Grant

PROJECT SUMMARY Neurodevelopmental disorders such as autism spectrum disorder present a particular challenge due to the complex nature of clinical symptoms and etiology. To understand and dissect human disorders, animal models provide valuable insights that can lead to novel therapeutics and/or drive public health decisions. To facilitate this critical level of comprehension, the mouse model has significantly progressed our understanding of how in utero exposure to common toxins, such as bisphenol A (BPA), can disrupt neural development. Tremendous progress has been made using this model to elucidate the toxin-related pathophysiology. In particular, the mouse model is highly valuable due to the relative evolutionary similarity between rodents and humans. That said, other models, specifically zebrafish (Danio rerio), can complement murine systems because of their unique set of biological attributes and the technologies that have been developed to exploit these biological advantages. Unlike mammalian development, zebrafish development is rapid and external. When seeking to understand neurodevelopmental disorders, these factors provide significant benefits in determining where and when critical periods of dysfunction might occur. Zebrafish also have a relatively reduced nervous system, at least early in development, and are translucent. These factors provide crucial advantages to both identifying aberrant neural circuits and pinpointing cellular and systems-wide perturbations. Perhaps most importantly, the small size and high fecundity of zebrafish facilitate high-throughput screens that can be used to develop novel therapeutics. To further understand how toxins like BPA disrupt neural development, this project seeks to determine the effects of BPA exposure at behavioral and synaptic levels. Behavioral assays used in this project are amenable to high-throughput screens and are mediated by well-annotated and restricted neural circuits. This should expedite investigations at the level of the synapse, another goal of this project. Finally, the project seeks to understand the cellular and molecular mechanisms underlying BPA-mediated pathophysiology and rescue deficits due to this exposure.