Yellen Lab Research Interests
Neuronal Metabolism and Excitability
These projects are inspired by a remarkably effective but poorly understood therapy for epilepsy: the ketogenic diet. This very-low-carbohydrate, high-fat diet is one of the oldest therapies for epilepsy, and it is still used today particularly for individuals with severe, drug-resistant epilepsy.
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.
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 sensors for ATP:ADP ratio and for NADH:NAD+ ratio, and are working on sensors for many other metabolites.
In collaboration with the lab of Dr. Nika Danial at HMS/DFCI, we have also discovered a non-diet manipulation of mouse metabolism that produces strong resistance to epileptic seizures in mice. The metabolic seizure resistance produced by genetic manipulation of the BAD protein requires functional KATP channels, supporting the notion that these channels are part of a valuable built-in antiseizure mechanism.