Our research is focused on understanding neuronal metabolism and how it is influenced by – and influences – neuronal activity and excitability

 

We aim to understand the fundamentals of neuronal metabolism, and this is not an abstract interest:  it is inspired by the remarkable ability of low-carbohydrate ketogenic diets to treat epilepsy.  Diet is a complex manipulation, and it no doubt affects brain excitability through many mechanisms, but we focus on the change in cellular fuel metabolism:  a switch from strong reliance on glucose to mixed use of both glucose and “ketone bodies”, small fuel molecules that become readily available during ketogenic diet.  We have learned that resistance to epileptic seizures can be produced in mice without a change in diet, by mutating a single gene that alters the balance of fuel use in neurons.  This metabolic seizure resistance connects altered metabolism to neuronal excitability by opening a specific class of ion channels, KATP channels.  We research the mechanism of this metabolic seizure resistance, and we would also like to reverse-engineer it to improve options for epilepsy treatment (particularly because ketogenic diet is easier to say than to do).

The pathways of cellular fuel metabolism have been known for many decades – but we still have much to learn about their physiology:  what is the ebb and flow in different metabolic pathways under different conditions?  Energy metabolism in the brain is very intense, using overall about 20% of the whole body’s fuel budget in a human; it is also highly dynamic, revving up in small regions of the brain and even in single neurons with increases in brain activity and energy demand.  We develop fluorescent biosensors of metabolism, and we use fast quantitative imaging of their signals in brain cells to provide a real-time readout of changes in cellular metabolism.

To complement the metabolic biosensors, we also use the deep chemical dimension of mass spectrometry imaging to monitor whole metabolic pathways in brain slices and to measure flux through these pathways with isotopically labeled fuel molecules. 

Improved understanding of the physiology of cellular metabolism has important further implications both in the nervous system – with a possible role in both neurodevelopmental and neurodegenerative diseases – and outside the nervous system, in cancer, diabetes, and obesity.