Schizophrenia-mimicking compounds such as phencyclidine (PCP) and MK801 are antagonists at the N-methyl-D-aspartate (NMDA) receptor and produce the whole spectrum of positive, negative, and cognitive symptoms. This is one of the most important pillars of the hypoglutamatergic hypothesis of schizophrenia. Since the synthesis of glutamate and GABA in neurons is closely connected to astrocyte metabolism, the study of astrocytic function is essential in this context. Dizocilpine-maleate (MK801) (0.5 mg/kg) was injected into rats every day for 6 days. The last dose was given together with [1-13 C]glucose and [1,2-13 C]acetate. Extracts from frontal, retrosplenial, and cingulate cortices (CRFC) and temporal lobes were examined by 13 C nuclear magnetic resonance spectroscopy, high pressure liquid chromatography, and light microscopy. In CRFC, significant increases in the levels of glutamate, glutathione, and taurine were seen, whereas amounts and turnover of noradrenaline, dopamine, and serotonin were unchanged. Glutamate and glutamine, derived from [1,2-13 C]acetate and thus astrocytes, were significantly decreased in CRFC as compared to controls. Labeling from [1-13 C]glucose and thus mostly neuronal metabolism was affected in the same brain region with decreased labeling of glutamate and GABA. The present model mimics the increased glutamate/glutamine activity found in drug-naive patients with first episode schizophrenia. Moreover, the decreased labeling indicates the transition to lower glutamatergic function seen in chronic schizophrenia patients. The disturbance in astrocytic function and the glutamine-glutamate-GABA cycle are of significant importance and might add to the malfunction of the cortico-striato-thalamo-cortical loop caused by NDMA receptor blockade.

A better understanding is needed of how glutamate metabolism is affected in mesial temporal lobe epilepsy (MTLE). Here we investigated glial-neuronal metabolism in the chronic phase of the kainate (KA) model of MTLE. Thirteen weeks following systemic KA, rats were injected i.p. with [1-(13)C]glucose. Brain extracts from hippocampal formation, entorhinal cortex, and neocortex, were analyzed by (13)C and (1)H magnetic resonance spectroscopy to quantify (13)C labeling and concentrations of metabolites, respectively. The amount and (13)C labeling of glutamate were reduced in the hippocampal formation and entorhinal cortex of epileptic rats. Together with the decreased concentration of NAA, these results indicate neuronal loss. Additionally, mitochondrial dysfunction was detected in surviving glutamatergic neurons in the hippocampal formation. In entorhinal cortex glutamine labeling and concentration were unchanged despite the reduced glutamate content and label, possibly due to decreased oxidative metabolism and conserved flux of glutamate through glutamine synthetase in astrocytes. This mechanism was not operative in the hippocampal formation, where glutamine labeling was decreased. In neocortex labeling and concentration of GABA were increased in epileptic rats, possibly representing a compensatory mechanism. The changes in the hippocampus might be of pathophysiological importance and merit further studies aiming at resolving metabolic causes and consequences of MTLE.

c-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 [1-13 C]glucose and the astrocyte-specific substrate [1,2-13 C]acetate. Synthesis of GABA from glutamine in the GABAergic synapses was further investigated in GAD65 knockout and wild-type mice using [1,2-13 C]acetate and in some cases c-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 B20%. 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. Blood Flow & Metabolism (2011) 31, 494-503; doi:10.1038/jcbfm.2010; published online 28 July 2010 Journal of Cerebral Keywords:13 C isotopes; g-vinylGABA (GVG, vigabatrin); glutamate decarboxylase; hypometabolism; neuronal-glial trafficking; nuclear magnetic resonance IntroductionThe most abundant neurotransmitters in the brain are glutamate and g-aminobutyric acid (GABA) for excitatory and inhibitory transmission, respectively.A tight regulation of the synthesis and degradation of these two compounds is therefore crucial. Disturbances in this regulation are likely involved in GABA-glutamate imbalances characteristic for a number of neurodegenerative and psychiatric disorders (Sonnewald and Kondziella, 2003). The GABA synthesis from glutamate is catalyzed by the enzyme glutamate decarboxylase (GAD, EC 4.1.1.15) of which two isoforms, GAD65 and GAD67, have been identified. These isoforms are encoded for by separate genes and differ with regard to regulation and intracellular localization (Erlander et al, 1991;Kaufman et al, 1991;Esclapez et al, 1994). The GAD65 appears to exist predominantly as a dormant apoenzyme, being rapidly activated on binding of pyridoxal phosphate. In contrast, GAD67 is present as the active holoenzyme having the coenzyme bound . The GAD67 is localized throughout the cytosol of GABAergic neurons, Correspondence: Dr HS Waagepetersen, Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, DK-2100 Copenhagen, Denmark. E-mail: hsw@farma.ku.dk 5 The major part of the wo...

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