Neuronal Metabolism and Excitability; Fluorescent Biosensor Imaging; K-ATP Channels and Anti-epilepsy Mechanisms

A major research focus of our 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. We are investigating the possible role of metabolically-sensitive Kchannels (KATP channels) in the mechanism of the diet, and learning about their basic role in neuronal firing. We have discovered that a change in fuel supply to brain cells, or in their genetic preference for certain fuels, can produce opening of KATP channels in various central neurons.  Opening of these channels slows action potential firing and may contribute to the anticonvulsant mechanism.

To investigate the metabolic events that lead to seizure resistance, and also to study the fundamental features of neural metabolism, we have developed a series of fluorescent biosensors of metabolism. These sensors allow us to visualize the local and time-varying changes of important molecules (like ATP or NADH) in living cells. We target these sensors to individual brain cells to learn how they respond dynamically to rapid changes in energy demand during brain activity, and how these responses change with variations in fuel supply and other alterations in metabolism. We use fluorescence lifetime imaging (FLIM) to get a quantitative readout of the sensors in acute brain slices or in vivo in the mouse brain.

Publications View
The dentate gyrus differentially metabolizes glucose and alternative fuels during rest and stimulation.
Authors: Authors: York EM, Miller A, Stopka SA, Martínez-François JR, Hossain MA, Baquer G, Regan MS, Agar NYR, Yellen G.
J Neurochem
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Spatially resolved metabolomics and isotope tracing reveal dynamic metabolic responses of dentate granule neurons with acute stimulation.
Authors: Authors: Miller A, York EM, Stopka SA, Martínez-François JR, Hossain MA, Baquer G, Regan MS, Agar NYR, Yellen G.
Nat Metab
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Spatially resolved metabolomics and isotope tracing reveal dynamic metabolic responses of dentate granule neurons with acute stimulation.
Authors: Authors: Miller A, York E, Stopka S, Martínez-François J, Hossain MA, Baquer G, Regan M, Agar N, Yellen G.
Res Sq
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Author Correction: Metabolic regulation of species-specific developmental rates.
Authors: Authors: Diaz-Cuadros M, Miettinen TP, Skinner OS, Sheedy D, Díaz-García CM, Gapon S, Hubaud A, Yellen G, Manalis SR, Oldham WM, Pourquié O.
Nature
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Metabolic regulation of species-specific developmental rates.
Authors: Authors: Diaz-Cuadros M, Miettinen TP, Skinner OS, Sheedy D, Díaz-García CM, Gapon S, Hubaud A, Yellen G, Manalis SR, Oldham WM, Pourquié O.
Nature
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Neurophotonic tools for microscopic measurements and manipulation: status report.
Authors: Authors: Abdelfattah AS, Ahuja S, Akkin T, Allu SR, Brake J, Boas DA, Buckley EM, Campbell RE, Chen AI, Cheng X, Cižmár T, Costantini I, De Vittorio M, Devor A, Doran PR, El Khatib M, Emiliani V, Fomin-Thunemann N, Fainman Y, Fernandez-Alfonso T, Ferri CGL, Gilad A, Han X, Harris A, Hillman EMC, Hochgeschwender U, Holt MG, Ji N, Kiliç K, Lake EMR, Li L, Li T, Mächler P, Miller EW, Mesquita RC, Nadella KMNS, Nägerl UV, Nasu Y, Nimmerjahn A, Ondrácková P, Pavone FS, Perez Campos C, Peterka DS, Pisano F, Pisanello F, Puppo F, Sabatini BL, Sadegh S, Sakadzic S, Shoham S, Shroff SN, Silver RA, Sims RR, Smith SL, Srinivasan VJ, Thunemann M, Tian L, Tian L, Troxler T, Valera A, Vaziri A, Vinogradov SA, Vitale F, Wang LV, Uhlírová H, Xu C, Yang C, Yang MH, Yellen G, Yizhar O, Zhao Y.
Neurophotonics
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Delivery of AAV for Expression of Fluorescent Biosensors in Juvenile Mouse Hippocampus.
Authors: Authors: Díaz-García CM, Nathwani N, Martínez-François JR, Yellen G.
Bio Protoc
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Quantitative in vivo imaging of neuronal glucose concentrations with a genetically encoded fluorescence lifetime sensor.
Authors: Authors: Díaz-García CM, Lahmann C, Martínez-François JR, Li B, Koveal D, Nathwani N, Rahman M, Keller JP, Marvin JS, Looger LL, Yellen G.
J Neurosci Res
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Neurons rely on glucose rather than astrocytic lactate during stimulation.
Authors: Authors: Díaz-García CM, Yellen G.
J Neurosci Res
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Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism.
Authors: Authors: Yellen G.
J Cell Biol
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