Characterization of β-Hydroxybutyrate as a Cell Autonomous Fuel for Active Excitatory and Inhibitory Neurons.

The ketogenic diet is a standard treatment for drug resistant epilepsy, but the mechanism of treatment efficacy is largely unknown. Changes to excitatory and inhibitory balance is one hypothesized mechanism. Here, we determine that ATP levels are differentially higher in inhibitory neurons compared to excitatory neurons, suggesting that greater mitochondrial ATP production in inhibitory neurons could be one mechanism mediating therapeutic benefit. Further, our studies of ketone metabolism by synaptic mitochondria should inform management of side effects and risks associated with ketogenic diet treatments. These results provide novel insights that clarify the role of ketones at the cellular level in ketogenic diet treatment for intractable epilepsy and inform the use of ketogenic diets for neurologic and psychiatric conditions more broadly.