Ketosis and brain handling of glutamate, glutamine, and GABA

Abstract

We hypothesize that one mechanism of the anti-epileptic effect of the ketogenic diet is to alter brain handling of glutamate. According to this formulation, in ketotic brain astrocyte metabolism is more active, resulting in enhanced conversion of glutamate to glutamine. This allows for: (a) more efficient removal of glutamate, the most important excitatory neurotransmitter; and (b) more efficient conversion of glutamine to GABA, the major inhibitory neurotransmitter.

Fig. 1. The Glutamate-Glutamine Cycle

The Glutamate-Glutamine Cycle. This mechanism cycle accomplishes (a) removal of glutamate from the synapse via uptake into astrocytes, which (b) convert glutamate to glutamine via glutamine synthetase, a glial enzyme; (c) glutamine export to neurons, which (d) hydrolyze this amino acid to glutamate, thereby replenishing the glutamate that neurons release to the synapse. In addition, glutamate can be converted to GABA, a major inhibitory neurotransmitter, and to aspartate. Left: function of the cycle in the basal state. Right: the cycle in ketosis. We hypothesize that in ketotic brain there occurs: (a) activation of astrocytic metabolism, resulting in enhanced conversion of glutamate to glutamine and providing more glutamine to serve as precursor to GABA; and (b) relatively less transamination of glutamate to yield aspartate and relatively more conversion of glutamate to GABA.