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.

Public Health Relevance

? relevance to public health This project will address the role of metabolically-sensitive potassium channels (K{ATP}) expressed in cortical neurons. K{ATP} channels have been implicated in the regulation of the cortical (<1 Hz) slow oscillation ? a major component of sleep[4]. Additionally, K{ATP} channel activity is increased by metabolites of the ketogenic diet[5], an effective treatment for epilepsy[44]. Understanding how K{ATP} channels regulate the slow oscillation will broaden our understanding of sleep and potentially reveal how these channels may contribute to the anticonvulsant action of the ketogenic diet.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F03B-G (20))
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Stewart, Randall R
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Harvard University
Schools of Medicine
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Lutas, Andrew; Lahmann, Carolina; Soumillon, Magali et al. (2016) The leak channel NALCN controls tonic firing and glycolytic sensitivity of substantia nigra pars reticulata neurons. Elife 5:
Lutas, Andrew; Birnbaumer, Lutz; Yellen, Gary (2014) Metabolism regulates the spontaneous firing of substantia nigra pars reticulata neurons via KATP and nonselective cation channels. J Neurosci 34:16336-47
Lutas, Andrew; Yellen, Gary (2013) The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci 36:32-40
Giménez-Cassina, Alfredo; Martínez-François, Juan Ramón; Fisher, Jill K et al. (2012) BAD-dependent regulation of fuel metabolism and K(ATP) channel activity confers resistance to epileptic seizures. Neuron 74:719-30