title: Quantification of the GABA shunt and the importance of the GABA shunt versus the 2-oxoglutarate dehydrogenase pathway in GABAergic neurons.
abstract: We investigated the activity of the cerebral GABA shunt relative to the overall cerebral tricarboxylic acid (TCA) cycle and the importance of the GABA shunt versus 2-oxoglutarate dehydrogenase for the conversion of 2-oxoglutarate into succinate in GABAergic neurons. Awake mice were dosed with [1-(13)C]glucose, and brain extracts were analyzed by 13C NMR spectroscopy. The percent enrichments of GABA C-2 and glutamate C-4 were the same: 5.0 +/- 1.6 and 5.1 +/- 0.2%, respectively (mean +/- SD). This, together with previous data, indicates that the flux through the GABA shunt relative to the overall cerebral TCA cycle flux equals the GABA/glutamate pool size ratio, which in the mouse is 17%. It has previously been shown that under the experimental conditions used in this study, the 13C labeling of aspartate from [1-(13)C]-glucose specifically reflects the metabolic activity of GABAergic neurons. In the present study, the reduction in the formation of [13C]aspartate during inhibition of the GABA shunt by gamma-vinyl-GABA indicated that not more than half the flux from 2-oxoglutarate to succinate in GABAergic neurons goes via the GABA shunt. Therefore, because fluxes through the GABA shunt and 2-oxoglutarate dehydrogenase in GABAergic neurons are approximately the same, the TCA cycle activity of GABAergic neurons could account for one-third of the overall cerebral TCA cycle activity in the mouse. Treatment with gamma-vinyl-GABA, which increased GABA levels dramatically, caused changes in the 13C labeling of glutamate and glutamine, which indicated a reduction in the transfer of glutamate from neurons to glia, implying reduced glutamatergic neurotransmission. In the most severely affected animals these alterations were associated with convulsions.
authors.affiliation: Division for Environmental Toxicology, Norwegian Defence Research Institute, Kjeller, Norway.
authors.forename: B
authors.initials: B
authors.lastname: Hassel
authors.forename: C U
authors.initials: CU
authors.lastname: Johannessen
authors.forename: U
authors.initials: U
authors.lastname: Sonnewald
authors.forename: F
authors.initials: F
authors.lastname: Fonnum
mesh_terms: D019342:Acetic Acid / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D002952:Citric Acid Cycle; D005260:Female; D005947:Glucose / Q000378:metabolism; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000201:enzymology* / Q000378:metabolism* / Q000502:physiology; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology
chemical_list: D000596:Amino Acids; D005680:gamma-Aminobutyric Acid; D000641:Ammonia; D007655:Ketoglutarate Dehydrogenase Complex; D020888:Vigabatrin; D005947:Glucose; D019342:Acetic Acid