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.
? 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.
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 |