A primary mechanism for efficacy of the ketogenic diet may be energy repletion at the tripartite synapse.

The ketogenic diet is a well-known treatment for epilepsy. Despite decades of research, it is not yet known how the diet accomplishes its anti-seizure efficacy. One of the earliest proposed mechanisms was that the ketogenic diet is able to replenish cellular energy stores in the brain. Although several mechanisms have been suggested for how energy depletion may contribute to seizure generation and epileptogenesis, how the dynamics of energy depletion actually leads to abnormal electrical activity is not known.In this work, we investigated the behavior of the tripartite synapse using a recently developed neurochemical model, which was modified to include ketone chemistry. We ran transient, non-steady-state simulations mimicking normoglycemia and ketosis for metabolic conditions known to be clinically treated with the ketogenic diet, as well as a condition for which the ketogenic diet was not effective clinically.We found that reduction in glucose, as well as pathological decreases in the activity of glucose transporter 1, pyruvate dehydrogenase complex, monocarboxylate transporter 1 (MCT1), and mitochondrial complex I, all led to functioning of the tripartite synapse in a rapid burst-firing mode suggestive of epileptiform activity. This was rescued by the addition of the ketone D--hydroxybutyrate in the glucose deficit, glucose transporter 1 deficiency, and pyruvate dehydrogenase complex deficiency, but not in MCT1 deficiency or mitochondrial complex I deficiency.We demonstrated that replenishment of cellular energy stores is a feasible mechanism for the efficacy of the ketogenic diet. Although we do not rule out other proposed mechanisms, our work suggests that cellular energy repletion may be the primary action of the ketogenic diet. Further study of the contribution of energy deficits to seizure onset and even epileptogenesis may yield novel therapies for epilepsy in the future.