Metabolic and KATP channel regulation of the cortical slow oscillation

Harvard Medical School, Boston MA

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Linked publications & trials

Abstract

This project will examine the role of metabolically-sensitive potassium channels (KATP) in the cortex. These channels have recently been shown to regulate a cortical (<1 Hz) slow oscillation. During deep sleep stages or anesthesia, cortical neurons oscillate between two states: an up-state during which neurons are depolarized and a down-state during which neurons are hyperpolarized. Potassium channels are believed to be important for the transition to the down-state and regulating the duration of the two states. In particular, the KATP channel has been shown to be important in regulating the slow oscillation. Since KATP channels couple cellular metabolism to the electrical state of the cell, it is likely that metabolism can regulate the cortical slow oscillation. We propose to further characterize the role of KATP channels in controlling cortical network activity using an in vitro model of the slow oscillation. In aim 1, we will identify populations of cortical neurons that express functional KATP channels using patch-clamp electrophysiology strategies. In aim 2, we will characterize the ability of KATP channels to regulate the duration of up-states and down- states in mouse brain slices using pharmacological and genetic manipulation of KATP channels. In aim 3, we will determine the contribution of cellular metabolism to the regulation of the oscillation by providing different energy fuels, particularly ketone bodies that may alter KATP channel activity. These proposed studies aim to use the slow oscillation to test the ability of ketone body metabolism to alter KATP channel activity and network excitability. This work will have significant importance in understanding the role of KATP channels in the brain where they may contribute to the anticonvulsant properties of nutritional therapies for epilepsy, such as the ketogenic diet.