期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 31, 期 2, 页码 494-503出版社
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2010.115
关键词
C-13 isotopes; gamma-vinylGABA (GVG, vigabatrin); glutamate decarboxylase; hypometabolism; neuronal-glial trafficking; nuclear magnetic resonance
资金
- Novo Nordisk Foundation
- Novo Nordisk
- Horslev
- Lundbeck Foundations
gamma-Aminobutyric acid (GABA) synthesis from glutamate is catalyzed by glutamate decarboxylase (GAD) of which two isoforms, GAD65 and GAD67, have been identified. The GAD65 has repeatedly been shown to be important during intensified synaptic activity. To specifically elucidate the significance of GAD65 for maintenance of the highly compartmentalized intracellular and intercellular GABA homeostasis, GAD65 knockout and corresponding wild-type mice were injected with [1-C-13] glucose and the astrocyte-specific substrate [1,2-C-13] acetate. Synthesis of GABA from glutamine in the GABAergic synapses was further investigated in GAD65 knockout and wild-type mice using [1,2-C-13] acetate and in some cases gamma-vinylGABA (GVG, Vigabatrin), an inhibitor of GABA degradation. A detailed metabolic mapping was obtained by nuclear magnetic resonance (NMR) spectroscopic analysis of tissue extracts of cerebral cortex and hippocampus. The GABA content in both brain regions was reduced by similar to 20%. Moreover, it was revealed that GAD65 is crucial for maintenance of biosynthesis of synaptic GABA particularly by direct synthesis from astrocytic glutamine via glutamate. The GAD67 was found to be important for synthesis of GABA from glutamine both via direct synthesis and via a pathway involving mitochondrial metabolism. Furthermore, a severe neuronal hypometabolism, involving glycolysis and tricarboxylic acid (TCA) cycle activity, was observed in cerebral cortex of GAD65 knockout mice. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 494-503; doi: 10.1038/jcbfm.2010.115; published online 28 July 2010
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