Grant: Doctoral: Vanier Canada Graduate Scholarships

The milieu of voltage-gated ion channels in a neuron controls signal transmission within the central nervous system. Dysregulation of one voltage-gated potassium channel in particular, Kv1.2, can have catastrophic consequences, from severe movement disorders to epileptic encephalopathy and intellectual disability. At the molecular level, Kv1.2 is uniquely regulated in a pulse-by-pulse manner, which allows these channels to increase their activity when challenged with repetitive stimulation. An important consequence of this mechanism, termed use-dependent activation (UDA), is that it can act as a self-silencing mechanism for hyperactive neurons. My research project aims to understand this regulatory mechanism and its role in controlling neuronal activity. At the molecular level, I have made major strides towards identifying and characterizing the specific regulatory factors responsible for generating UDA in Kv1.2. I will also examine the influence of Kv1.2 and UDA at the neuronal level by measuring their influence on neuronal growth and action potential firing properties. Lastly, I will examine the impact of altering UDA in a genetically modified mouse. I expect this will have severe physiological consequences because Kv1.2 is necessary for survival, and UDA has a profound impact on Kv1.2 channel function. Overall, this project will describe a new mechanism that regulates brain activity, at molecular/cellular level and in the context of whole animal physiology. These findings are significant because they may elucidate a new target to modulate seizure disorders and other diseases of electrical excitability in humans.