NIH VideoCast - Cellular Metabolism in the Brain and Resistance to Epileptic Seizures

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Cellular Metabolism in the Brain and Resistance to Epileptic Seizures

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Air date:	Monday, April 4, 2016, 12:00:00 PM Time displayed is Eastern Time, Washington DC Local
Views:	Total views: 396 (32 Live, 364 On-demand)
Category:	Neuroscience
Runtime:	01:04:27
Closed captioning:	Check box to display CC outside of the video Note: You can drag the captioning window around and resize it
Description:	NIH Neuroscience Series Seminar A major research focus of Dr. Yellen’s lab was inspired by a remarkably effective but poorly understood therapy for epilepsy: the ketogenic diet. Used mainly for the many patients with drug-resistant epilepsy, this high fat, very low carbohydrate diet produces a dramatic reduction or elimination in seizures for most patients. They are investigating the possible role of metabolically-sensitive K+ channels (KATP channels) in the mechanism of the diet, and learning about their basic role in neuronal firing. They have discovered that certain fuel molecules that appear in the blood of people on the ketogenic diet – ketone bodies – can produce opening of KATP channels in various central neurons, which slows action potential firing and may contribute to the anticonvulsant mechanism. How does ketone body metabolism lead to KATP channel opening? Their main hypothesis is that ketone bodies, or other metabolic manipulations, lead to a shift from glycolytic metabolism to other mechanisms of ATP production, and that glycolytic ATP production is particularly effective in preventing KATP channels from opening. To investigate this hypothesis and other questions in cellular metabolism, they are developing a series of fluorescent biosensors. Their first such sensor lets them visualize the local ratio of ATP:ADP in living cells. They are targeting this sensor to different cellular locations (plasma membrane, cytoplasm, mitochondria) to learn how energy production and consumption varies locally within neurons and other cells. They are also working on sensors for the basic metabolites NADH and NADPH, to get a more complete picture of metabolic regulation. This research involves electrophysiology and imaging of cultured neurons and brain slices. They also use knockout mice to investigate specific hypotheses about the connection between neuronal metabolism, excitability, and seizures. They also study the “moving parts” of functional ion channel proteins using single channel biophysics and directed mutagenesis. One strategy they use is to introduce individual cysteine residues into the channel protein; these cysteines serve as targets for chemical modification and for metal binding. Their ability to modify the introduced cysteines in different conformational states gives specific information about the functional motions of the protein. These methods are now being applied to elucidate the unusual gating of pacemaker channels, which are important generators of rhythmic electrical behavior in the heart and brain.

NLM Title:	Cellular metabolism in the brain and resistance to epileptic seizures / Gary Yellen.
Author:	Yellen, Gary. National Institutes of Health (U.S.),
Publisher:
Abstract:	(CIT): A major research focus of Dr. Yellen's lab was inspired by a remarkably effective but poorly understood therapy for epilepsy: the ketogenic diet. Used mainly for the many patients with drug-resistant epilepsy, this high fat, very low carbohydrate diet produces a dramatic reduction or elimination in seizures for most patients. They are investigating the possible role of metabolically-sensitive K+ channels (KATP channels) in the mechanism of the diet, and learning about their basic role in neuronal firing. They have discovered that certain fuel molecules that appear in the blood of people on the ketogenic diet - ketone bodies - can produce opening of KATP channels in various central neurons, which slows action potential firing and may contribute to the anticonvulsant mechanism. How does ketone body metabolism lead to KATP channel opening? Their main hypothesis is that ketone bodies, or other metabolic manipulations, lead to a shift from glycolytic metabolism to other mechanisms of ATP production, and that glycolytic ATP production is particularly effective in preventing KATP channels from opening. To investigate this hypothesis and other questions in cellular metabolism, they are developing a series of fluorescent biosensors. Their first such sensor lets them visualize the local ratio of ATP:ADP in living cells. They are targeting this sensor to different cellular locations (plasma membrane, cytoplasm, mitochondria) to learn how energy production and consumption varies locally within neurons and other cells. They are also working on sensors for the basic metabolites NADH and NADPH, to get a more complete picture of metabolic regulation. This research involves electrophysiology and imaging of cultured neurons and brain slices. They also use knockout mice to investigate specific hypotheses about the connection between neuronal metabolism, excitability, and seizures. They also study the "moving parts" of functional ion channel proteins using single channel biophysics and directed mutagenesis. One strategy they use is to introduce individual cysteine residues into the channel protein; these cysteines serve as targets for chemical modification and for metal binding. Their ability to modify the introduced cysteines in different conformational states gives specific information about the functional motions of the protein. These methods are now being applied to elucidate the unusual gating of pacemaker channels, which are important generators of rhythmic electrical behavior in the heart and brain.
Subjects:	Anticonvulsants--pharmacokinetics Brain--metabolism Diet, Ketogenic Drug Resistant Epilepsy--diet therapy Drug Resistant Epilepsy--metabolism
Publication Types:	Lecture Webcast

NLM Classification:	WL 385
NLM ID:	101682303
CIT Live ID:	17448
Permanent link:	https://videocast.nih.gov/watch=17448