Epilepsy affects roughly 1% of the human population. For the one third of patients who cannot achieve adequate seizure control with existing medications, one effective alternative is dietary treatment with a high fat and very low carbohydrate ketogenic diet (KD). The KD can be remarkably effective, with ~1/3 of patients becoming seizure free, but the strict diet regimen is difficult for patients to comply with. Learning the still mysterious mechanism of the KD would teach us how the brain may naturally protect itself against seizures, and also permit the design of better dietary treatments and better anticonvulsant medications. On the KD, the brain uses circulating ketone bodies (KB's, esp. 2 hydroxybutyrate and acetoacetate) as an alternate to the usual fuel source, glucose. This change in fuel source somehow produces an anticonvulsant action, but the link remains unknown. A good candidate is an ion channel well known for its sensitivity to metabolism the ATP sensitive K+ channel or KATP channel. Experiments on brain slices show that KBs can, on a fairly rapid time scale (10's of minutes) lead to slowing of spontaneous firing in cells of substantia nigra pars reticulata. KATP channels are important for this effect. The demonstration of a short term in vitro effect of ketone bodies on excitability, and the implication of KATP channels in the effect, offer a new avenue for investigating the mechanism of the ketogenic diet. We will follow up on this lead by asking how KATP channels function in two brain circuits important in epilepsy, and to learn more about possible mechanisms by which these channels may become activated with ketone body metabolism. Substantia nigra pars reticulata neurons and hippocampal dentate granule cells will be the main focus of this work. The effects of ketone bodies on KATP channels and other targets, such as gene expression, are likely due to changes in proximal consequences of the metabolic change. Optical probes for reactive oxygen species, for NADH, and for ATP will be used to learn how central neurons respond to excitation in the presence of different fuel molecules. These experiments will report on how metabolism changes during neuronal activation, and how this is affected by KBs, answering fundamental questions about brain metabolism and function.

Public Health Relevance

One of the best treatments for epilepsy (a seizure disorder affecting roughly 1% of the population) is a very low carbohydrate, high fat ketogenic diet. Because the diet is unpalatable and difficult, it would be useful to understand how it acts on brain cells so that better drug therapies (or easier diets) can be designed. This project will study how ketone bodies produced by the body during the diet act on brain cells to change their activity and prevent seizures, by examining electrical activity and metabolic changes in brain slices from rodents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055031-04
Application #
8021014
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Whittemore, Vicky R
Project Start
2008-02-15
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
4
Fiscal Year
2011
Total Cost
$327,030
Indirect Cost
Name
Harvard University
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Martínez-François, Juan Ramón; Fernández-Agüera, María Carmen; Nathwani, Nidhi et al. (2018) BAD and KATP channels regulate neuron excitability and epileptiform activity. Elife 7:
Yellen, Gary (2018) Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism. J Cell Biol 217:2235-2246
Foley, Jeannine; Burnham, Veronica; Tedoldi, Meghan et al. (2018) BAD knockout provides metabolic seizure resistance in a genetic model of epilepsy with sudden unexplained death in epilepsy. Epilepsia 59:e1-e4
Díaz-García, Carlos Manlio; Mongeon, Rebecca; Lahmann, Carolina et al. (2017) Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake. Cell Metab 26:361-374.e4
Hung, Yin P; Teragawa, Carolyn; Kosaisawe, Nont et al. (2017) Akt regulation of glycolysis mediates bioenergetic stability in epithelial cells. Elife 6:
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:
Mongeon, Rebecca; Venkatachalam, Veena; Yellen, Gary (2016) Cytosolic NADH-NAD(+) Redox Visualized in Brain Slices by Two-Photon Fluorescence Lifetime Biosensor Imaging. Antioxid Redox Signal 25:553-63
Yellen, Gary; Mongeon, Rebecca (2015) Quantitative two-photon imaging of fluorescent biosensors. Curr Opin Chem Biol 27:24-30
Hung, Yin Pun; Yellen, Gary (2014) Live-cell imaging of cytosolic NADH-NAD+ redox state using a genetically encoded fluorescent biosensor. Methods Mol Biol 1071:83-95
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

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