For those epileptic patients for whom conventional drugs poorly control their seizures, adoption of a high-fat, low-protein and -carbohydrate (“ketogenic”) diet offers some relief. Such a diet results in a high serum concentration of ketone bodies, such as acetoacetate, that can cross the blood-brain barrier; however, how these metabolic products might modulate the effects of excitatory or inhibitory neurotransmission to alleviate epileptic symptoms is unclear. Juge et al. used a reconstituted proteoliposome system to investigate the regulation of vesicular glutamate transporters (VGLUTs), which mediate the loading of the excitatory neurotransmitter glutamate into presynaptic vesicles. Uptake of glutamate into the proteoliposomes by VGLUT2 (in response to the ionophore valinomycin) required the presence of chloride ions (Cl–) in the buffer, as previously reported, but Cl– was not cotransported with glutamate. Hypothesizing that Cl– was allosterically regulating the activity of VGLUT2, the authors examined other compounds for their effects on glutamate transport and found a number of metabolic products, including acetoacetate, that inhibited the activity of VGLUT2 and increased its dependency on Cl–. Other members of the family of vesicular neurotransmitter transporters were also inhibitable by acetoacetate. Acetoacetate reversibly inhibited the release of glutamate from cultured rat hippocampal neurons but not astrocytes. The ketone body also reduced the quantal size of glutamate released from CA1 pyramidal cells in mouse hippocampal slices. Finally, in rats treated with the convulsant 4AP, acetoacetate reduced the intensity of seizures and the amount of secreted glutamate in the brain. Together, these data suggest that metabolic state might influence excitatory neurotransmission by regulating the activity of VGLUT proteins.
N. Juge, J. A. Gray, H. Omote, T. Miyaji, T. Inoue, C. Hara, H. Uneyama, R. H. Edwards, R. A. Nicoll, Y. Moriyama, Metabolic control of vesicular glutamate transport and release. Neuron 68, 99–112 (2010). [PubMed]