Collaborative Research: Nervous System Adaptations in a Highly Neurotoxic Organism

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Non-Technical ParagraphRough-skinned newts (Taricha granulosa) are among the most toxic animals known: some individuals possess enormous quantities of tetrodotoxin (TTX), which prevents brain cells (neurons) from signaling to each other. Scientists know a great deal about how TTX normally blocks neural activity, but not much about how animals that possess TTX are able to resist its effects. The ability of newts to resist TTX is particularly puzzling because several of their genes must be mutated in concert, as a mutation in only one affected gene would leave the newt vulnerable to TTX's affects, and likely dead. Strangely, newts are not simply resistant to TTX's effects, but are actually attracted to the smell of TTX. In the proposed work, the team will use well-established methods to quantify the distribution of TTX inside newts' bodies, identify mutations that are likely involved in TTX resistance, examine the effects of TTX on their neurons, and discover how the neurons involved in smelling are activated by TTX. This basic research will help scientists understand how neurons work at a molecular level, which will increase or understanding of the "nuts and bolts" of healthy brain function, as well as how animals adapt to the presence of toxins. Undergraduate students from under-represented groups, including students from Native American populations in Oregon, will be recruited to participate in summer research programs associated with the work. These experiences will help prepare a diverse population of students for future careers in STEM related fields.Technical ParagraphTTX is toxic because it blocks voltage-gated sodium channels (NaVs), essential for the generation and propagation of action potentials. The proposed work will identify where the different forms of NaVs are expressed in neurons and muscles in newts, identify specific mutations in these channels that allow them to resist the toxic effects of TTX, and determine how these structural changes alter neuron function. Using analytical chemistry, histochemistry, and molecular biology, levels of TTX in different tissues as well as the location and structure of the six different NaVs will be examined in both highly toxic and non-toxic newts to quantify levels of TTX resistance and identify mutations that confer resistance. The electrophysiological properties of NaVs in a heterologous expression system and of neurons in the brain of newts will be characterized to determine whether and how TTX resistance alters channel and neuron function. In addition, using a combination of techniques, the adaptations underlying TTX detection in the olfactory epithelium will be identified to understand how this unusual ability evolved. The proposed work will contribute to understanding a physiologically vital class of ion channels, as well as the ways in which evolution at the molecular level shapes nervous system function and animal behavior, thereby deepening our understanding of how neurons function and change over evolutionary time. In addition, the proposed work will immerse undergraduate students in the nature and practice of science, particularly through the involvement of Williamette University students in an REU program at Michigan State University.