Metabolic and KATP channel regulation of the cortical slow oscillation

Harvard Medical School, Boston MA

Investigators

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Abstract

Project Summary/Abstract This project will examine the role of metabolically-sensitive potassium channels (K{ATP}) 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 K{ATP} channel has been shown to be important in regulating the slow oscillation. Since K{ATP} 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 K{ATP} 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 K{ATP} channels using patch-clamp electrophysiology strategies. In aim 2, we will characterize the ability of K{ATP} channels to regulate the duration of up-states and downstates in mouse brain slices using pharmacological and genetic manipulation of K{ATP} 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 K{ATP} channel activity. These proposed studies aim to use the slow oscillation to test the ability of ketone body metabolism to alter K{ATP} channel activity and network excitability. This work will have significant importance in understanding the role of K{ATP} channels in the brain where they may contribute to the anticonvulsant properties of nutritional therapies for epilepsy, such as the ketogenic diet.