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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS077633-03
Application #
8513432
Study Section
Special Emphasis Panel (ZRG1-F03B-G (20))
Program Officer
Stewart, Randall R
Project Start
2011-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$29,591
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Lutas, Andrew; Yellen, Gary (2013) The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci 36:32-40