The long-term objective of this application is to understand how specific types of ion channels contribute to the physiology of cortical neurons and by doing so provide possible insights into how dysfunction of specific ion channels leads to diseases such as epilepsy. This proposal is focused on the Kv1 subfamily of voltagegated potassium channels in a prominent class of neocortical inhibitory interneurons called fast-spiking (FS) cells. FS cells are the most prominent source of inhibition in the cortex. These cells have important roles in regulating excitation in the cortex. Moreover, dysfunction in these cells has been associated with a number of pathologies such as epilepsy and schizophrenia. Mutations in Kv1 proteins such as Kv1.1 are associated with neuropathology and epilepsy in humans. Removal of the Kv1.1 gene in the mouse produces profound epilepsy, however, the cellular basis of this phenotype is not understood. Findings are presented here that show that Kv1.1 protein in the cortex is most prominently expressed in FS interneurons, and Kv1.1- containing channels have a critical role in the regulation of activity in these cells. Understanding the functional roles of Kv1 channels in this important class of inhibitory interneurons is therefore required to elucidate the possible contribution of Kv1 channels in these cells to hyperexcitability and epilepsy.
Two specific aims are proposed in order to characterize the contribution of Kv1 channels to the physiology of FS cells. The first is to determine the functional role of Kv1 channels in regulating action potential generation in FS cells. This will be accomplished by recording from FS cells in brain slices and using pharmacological and genetic approaches to isolate the contribution of Kv1 channels to their excitability.
The second aim i s to determine the molecular composition of Kv1-mediated currents by combining immunohistochemistry, Kv1-subunit specific antibodies, and confocal microscopy. These studies are critical in establishing the roles of these channels in regulating inhibition in the cortex.
Epilepsy affects over three million Americans and thus represents a significant impact to public health. The goal of this study is to understand the normal physiological role of a specific subfamily of proteins that when mutated can produce epilepsy. This research focuses on the role of these proteins in inhibitory cells in the cortex and is a contribution to understanding the pathophysiology of epilepsy in humans.
| Clark, Brian D; Goldberg, Ethan M; Rudy, Bernardo (2009) Electrogenic tuning of the axon initial segment. Neuroscientist 15:651-68 |
