The brain encodes information in the form of electrical impulses called action potentials that are continuously exchanged between neurons. As brains age, the transmission of Action Potentials becomes less efficient. It is not understood why this occurs, but one possibility is that over time, neurons accumulate highly toxic molecules known as reactive oxygen species (ROS). There is support for the idea that ROS oxidize potassium channel proteins whose function is to permit movement of potassium ions through the membranes of neurons. Potassium ion movements are involved in the propagation of action potentials by neurons. This project will directly test the hypothesis that oxidation of potassium channels by ROS leads to cognitive impairment by hindering the transmission of Action Potentials. The PI will integrate research activities and outcomes into formal lectures on the neuroscience of aging. The project will provide research training opportunities for undergraduate, graduate, underrepresented and summer students. The Principal Investigator will present a series of lectures to middle and high school students as part of the Science, Medicine and Related Topics (SMART) program, whose mission is to advance the understanding and appreciation of science among underrepresented students.
The KCNB1 potassium channel is abundantly expressed in the brain and is susceptible to oxidation by ROS. When a cysteine residue is replaced with an alanine (C73A), oxidation is abolished. Based on this observation, a transgenic mouse expressing the non-oxidable KCNB1 variant (C73A) has been constructed. The effects of ROS on KCNB1 channels and the impact of this process on cognitive function will be determined by studying cognitive function in aging C73A mice. Behavioral tests will be performed to see whether the lack of oxidation of KCNB1 improves the ability of mice to learn and remember new tasks. Changes in behavior will be correlated with changes in the electrical activity of the brain which will be recorded using state of the art electrophysiological techniques. Further, it will be determined whether the naturally occurring antioxidant, hydrogen sulfide, which is synthesized by neurons, can prevent oxidation of KCNB1 channels. It is expected that aging mice that harbor the C73A variant will exhibit less cognitive impairment and more normal electrical activity in cortex and hippocampus, two regions of the brain that are most affected by the activity of KCNB1.
