PiN Faculty Member - Gary Yellen, PhD

Gary Yellen, PhD

Professor of Neurobiology

Harvard Medical School
Department of Neurobiology
Warren Alpert Building, Room 328
200 Longwood Avenue
Boston, MA 02115
Tel: 617-432-0137
Fax: 617 432 0121
Email: gary_yellen@hms.harvard.edu
Visit my lab page here.



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 K+ channels (KATP channels) in the mechanism of the diet, and learning about their basic role in neuronal firing. We 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? 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 glycolytic ATP production is particularly effective in preventing KATP channels from opening.

Consistent with this idea, we also have a genetic mouse model that reproduces the metabolic seizure resistance of the ketogenic diet (in collaboration with the lab of Prof. Nika Danial at the Dana Farber Cancer Institute).  When the BAD phosphosignaling protein is deleted or mutated, it produces effects on cellular metabolism that are similar to the ketogenic diet:  cells (including neurons and astrocytes) become less good at metabolizing glucose and better at metabolizing ketone bodies.  Mice with such BAD mutations exhibit strong resistance to epileptic seizures.  Furthermore, the seizure resistance disappears when the principal pore-forming subunit of KATP channels is ablated, supporting a role for KATP channels in metabolic seizure resistance.

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 ratio of ATP:ADP, or NADH:NAD+ in living cells. We 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. 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.

Altogether, we use cellular electrophysiology, biosensor technology, and fluorescent brain imaging to study the connections between neuronal activity and metabolism and to learn the mechanism by which altered metabolism can produce resistance to epileptic seizures.



Last Update: 9/16/2020



Publications

For a complete listing of publications click here.

 

 



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