PROJECT SUMMARY/ABSTRACT
Mercury (Hg) is a known neurotoxin considered among the top ten chemicals of public health concern by the
World Health Organization. While the acute effects of Hg are well chronicled, the consequences of chronic,
low-dose exposure are less clear. Given that clinical symptoms of most psychiatric disorders do not emerge
until early adulthood, there is a critical need for better understanding of the neural cell types and circuits most
adversely impacted by adolescent Hg exposure, as well as the associated behavioral phenotypes. At the
molecular level, Hg irreversibly binds to catalytic selenium (Se) moieties present in antioxidant selenoenzymes,
leading to redox dysregulation, altered Ca2+ homeostasis, and mitochondrial dysfunction. Growing evidence
indicates that oxidative stress impedes maturation of GABAergic circuitry, resulting in a permanent imbalance
between excitatory and inhibitory neurotransmission. Moreover, among GABAergic cell types, fast-spiking,
parvalbumin-expressing interneurons (PVIs) are most acutely impacted by redox imbalance. The long-term
goal of this project is to better understand how interactions between Hg exposure and dietary Se status
influence maturation of excitatory-inhibitory balance and the risk of developing psychiatric disorders. Our
central hypothesis is that Hg-mediated inhibition of selenoenzyme activity during adolescence preferentially
impairs PVIs, leading to irreversible deficits in excitatory-inhibitory tone and behavior. Our research team has
expertise to definitively assess the effects of altered Se metabolism on molecular, immunohistological, and
behavioral indices in rodents, with innovative tools and assays established to successfully perform the
proposed studies. Our two specific aims are as follows: Aim #1: Determine the effects of Hg on Se-dependent
redox balance, excitatory-inhibitory tone, and electrophysiological activity in primary cortical cultures. Aim #2:
Characterize the immediate and long-term effects of subtoxic juvenile Hg exposure on brain, behavior, and gut
microbiota.
