Motor Neuron Award funded by Kathleen Toy Estate and Christopher Warren Hallam Bequest
The basis of hyper-excitability in upper motor neurons in a model of motor neuron disease.
Dr Mark Bellingham
University of Queensland
Co-Investigator: Dr Peter Noakes
Evidence from human motor neuron disease patients and from animal models of motor neurone disease suggests that both upper and lower motor neurones may generate higher than normal levels of activity, and this hyperactivity may play a role in neuron death in motor neurone disease. In contrast to the extensive research carried out on lower motor neurones in animal models of motor neurone disease, little is known about changes in activity in upper motor neurones in these animal models. One reason for this is that upper motor neurones are only a fraction of cortical neurones, and it is consequently difficult to positively identify the upper motor neurones in experimental research. My research has already shown that lower motor neurones show hyper-activity from birth in an animal model of this disease, and this hyper-activity is associated with an increase in a specific type of sodium current and with increased levels of several sodium channel genes. Whether this early hyper-excitability also exists in upper motor neurones is unknown. The aim of this grant is to develop a novel animal model, in which upper motor neurones are positively identified due to their selective expression of a fluorescent protein marker, and then to test the hypothesis that early hyper-excitability, due to this increased sodium current, is present in upper motor neurones in this novel animal model of motor neurone disease. The electrical activity of upper motor neurones and the levels of expression of sodium channel genes and proteins will then be measured for the first time in these novel animals. This work will strengthen the evidence for hyperactivity as a factor in motor neurone disease, and may ultimately lead to novel therapeutic strategies.