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Neuronal Metabolism and Excitability
These projects are inspired by a remarkably effective but poorly understood therapy for epilepsy: the ketogenic diet. We have discovered that certain fuel molecules that appear in the blood of people on the ketogenic diet – ketone bodies – can produce opening of metabolically sensitive KATP channels in various central neurons. Opening of these potassium channels slows action potential firing and may contribute to the anticonvulsant mechanism. Our 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 this shift away from glycolytic ATP production is particularly effective in allowing KATP channels (which are inhibited by ATP) to open.
We aim to learn:
When are neuronal KATP channels active, and how do they influence firing and seizures?
Is ATP locally compartmented in neurons? In particular, does glycolysis govern ATP:ADP in the submembrane space sensed by KATP channels?
How does neuronal metabolism vary with fuel source?
What other signals or metabolic changes shift the balance between glycolysis and other metabolic pathways?
How does astrocyte metabolism influence neuronal metabolism?
We use electrophysiological and pharmacologic tools, as well as knockout mice. We also are developing a series of new fluorescent biosensors for visualizing metabolite levels in cells -- we already have a sensor for ATP:ADP ratio, and are working on sensors for NADH and NADPH.
In the long run, we would like to understand what it is about the ketogenic diet that prevents epileptic seizures. Because diets (and especially this diet) are notoriously difficult for people to follow, we hope that understanding the physiological basis of such therapy allows us either to fine-tune the dietary manipulation or to find medications that target the same very effective anticonvulsant mechanisms tapped into by the ketogenic diet.
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biorxiv(2023)
Margarete Diaz-Cuadros,Teemu P Miettinen,Owen S Skinner, Dylan Sheedy,Carlos Manlio Díaz-García, Svetlana Gapon, Alexis Hubaud,Gary Yellen,Scott R Manalis, William M Oldham,Olivier Pourquié
Natureno. 7956 (2023)
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Research squareno. 10 (2023): 1820-1835
Ketogenic Diet and Metabolic Therapiespp.321-335, (2022)
bioRxiv (Cold Spring Harbor Laboratory) (2022)
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