Grant: Discovery Grants Program - Individual

The cerebellum, which is Latin for ""little brain"", is an area of the brain essential for fine-tuning complex movements. It is also important for motor learning, i.e. reinforcing movements that are advantageous. Arguably, the most important cells in the cerebellum that are responsible for these effects are Purkinje neurons, and they are an integral part of motor learning theory. Many specific genes and proteins are believed to contribute to the normal functions of Purkinje neurons at a molecular level. I plan to focus my studies on two proteins in particular, carbonic anhydrase type 8 protein (CAR8) and aldolase C. These protein families generally have enzymatic activity, and are important for pH balance and energy generation, respectively. However, CAR8 and aldolase C appear to have different roles in the cerebellum. In one portion of this research program we will study mice that have a mutation in the gene for CAR8, which exhibit a wobbly side-to-side movement, and are appropriately named waddles (wdl) mice. Using these mice, we will determine the physiological effects of a lack of CAR8 at the cellular level and study the effects of this mutation with well-established motor learning behavioural tests. These experiments will greatly enhance our understanding of genes and proteins that are necessary for normal motor coordination, thereby providing a major advancement in the field. In a second portion of the research program we will analyze the protective effects of aldolase C. Interestingly, only about one-third of Purkinje neurons express high levels of aldolase C, and those cells are more likely to survive insults such as ischemic stroke and traumatic brain injury, than cells that do not express this protein. We have outlined a series of experiments in order to determine how this naturally occurring neuroprotective system works. The results should allow us to determine how to take advantage of this system, or how it could be manipulated, in order to protect other types of cells from traumatic insults. This may have implications for individuals who have suffered from stroke or trauma, as motor dysfunction is often associated with these types of pathologies.