Altered 13C glucose metabolism in the cortico-striato-thalamo-cortical loop in the MK-801 rat model of schizophrenia

Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism (Impact Factor: 5.41). 11/2010; 31(3):976-85. DOI: 10.1038/jcbfm.2010.193
Source: PubMed


Using a modified MK-801 (dizocilpine) N-methyl-D-aspartic acid (NMDA) receptor hypofunction model for schizophrenia, we analyzed glycolysis, as well as glutamatergic, GABAergic, and monoaminergic neurotransmitter synthesis and degradation. Rats received an injection of MK-801 daily for 6 days and on day 6, they also received an injection of [1-(13)C]glucose. Extracts of frontal cortex (FCX), parietal and temporal cortex (PTCX), thalamus, striatum, nucleus accumbens (NAc), and hippocampus were analyzed using (13)C nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, and gas chromatography-mass spectrometry. A pronounced reduction in glycolysis was found only in PTCX, in which (13)C labeling of glucose, lactate, and alanine was decreased. (13)C enrichment in lactate, however, was reduced in all areas investigated. The largest reductions in glutamate labeling were detected in FCX and PTCX, whereas in hippocampus, striatum, and Nac, (13)C labeling of glutamate was only slightly but significantly reduced. The thalamus was the only region with unaffected glutamate labeling. γ-Aminobutyric acid (GABA) labeling was reduced in all areas, but most significantly in FCX. Glutamine and aspartate labeling was unchanged. Mitochondrial metabolites were also affected. Fumarate labeling was reduced in FCX and thalamus, whereas malate labeling was reduced in FCX, PTCX, striatum, and NAc. Dopamine turnover was decreased in FCX and thalamus, whereas that of serotonin was unchanged in all regions. In conclusion, neurotransmitter metabolism in the cortico-striato-thalamo-cortical loop is severely impaired in the MK-801 (dizocilpine) NMDA receptor hypofunction animal model for schizophrenia.

Download full-text


Available from: Asta Kristine Håberg, Sep 30, 2015
34 Reads
  • Source
    • "If all lactate is from glucose directly, the enrichment in lactate should reflect that of glucose. However, experiments in which rats are injected with [1- 13 C]glucose this was not the case (Eyjolfsson et al. 2011). Lactate was approximately 10% less labelled than expected, fitting well with a cataplerotic production of lactate from vesicular glutamate which has a slower turnover of 13 C label than the glutamate pool which is in direct equilibrium with the TCA cycle (Waagepetersen et al. 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The central process in energy production is the oxidation of acetyl-CoA to CO2 by the tricarboxylic acid (TCA, Krebs, citric acid) cycle. However, this cycle functions also as a biosynthetic pathway from which intermediates leave to be converted primarily to glutamate, GABA, glutamine and aspartate and to a smaller extent to glucose derivatives and fatty acids in brain. When TCA cycle ketoacids are removed they must be replaced to permit the continued function of this essential pathway, by a process termed anaplerosis. Since the TCA cycle cannot act as a carbon sink, anaplerosis must be coupled with cataplerosis; the exit of intermediates from the TCA cycle. The role of anaplerotic reactions for cellular metabolism in brain has been studied extensively. However, the coupling of this process with cataplerosis and the roles that both pathways play in the regulation of amino acid, glucose, and fatty acid homeostasis have not been emphasized. The concept of a linkage between anaplerosis and cataplerosis should be underscored, because the balance between these two processes is essential. The hypothesis that cataplerosis in brain is achieved by exporting lactate generated from TCA cycle intermediates into the blood and perivascular area, is presented. This shifts the generally accepted paradigm of lactate generation as simply derived from glycolysis to that of oxidation and might present an alternative explanation for aerobic glycolysis (AG). This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 07/2014; 131(4). DOI:10.1111/jnc.12812 · 4.28 Impact Factor
  • Source
    • "NRGN, like DAOA, is involved in glutamate pathway regulation and may mediate effect of hypoglutamatergic function with impact on neural substrates in schizophrenia [62,63]. Furthermore, recent work has shown that neurotransmitter metabolism may be severely impaired in cortico-thalamic networks within MK-801 hypoglutamatergic animal model for schizophrenia, which is consistent with thalamo-cortical morphological abnormalities in schizophrenia [64]. Previous neuropathological studies in schizophrenia have considered cortical thinning to be the result of reduction or loss of cell number, cell density, or neuropil and observed that there are cell specific or layer specific changes in different cortical regions in schizophrenia [65,66]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although the genome wide supported psychosis susceptibility neurogranin (NRGN) gene is expressed in human brains, it is unclear how it impacts brain morphology in schizophrenia. We investigated the influence of NRGN rs12807809 on cortical thickness, subcortical volumes and shapes in patients with schizophrenia. One hundred and fifty six subjects (91 patients with schizophrenia and 65 healthy controls) underwent structural MRI scans and their blood samples were genotyped. A brain mapping algorithm, large deformation diffeomorphic metric mapping, was used to perform group analysis of subcortical shapes and cortical thickness. Patients with risk TT genotype were associated with widespread cortical thinning involving frontal, parietal and temporal cortices compared with controls with TT genotype. No volumetric difference in subcortical structures (hippocampus, thalamus, amygdala, basal ganglia) was observed between risk TT genotype in patients and controls. However, patients with risk TT genotype were associated with thalamic shape abnormalities involving regions related to pulvinar and medial dorsal nuclei. Our results revealed the influence of the NRGN gene on thalamocortical morphology in schizophrenia involving widespread cortical thinning and thalamic shape abnormalities. These findings help to clarify underlying NRGN mediated pathophysiological mechanisms involving cortical-subcortical brain networks in schizophrenia.
    PLoS ONE 12/2013; 8(12):e85603. DOI:10.1371/journal.pone.0085603 · 3.23 Impact Factor
  • Source
    • "It has been well established that the rate of neurotransmitter cycling is stoichiometrically coupled to the neuronal glucose oxidation over the long range of brain activity indicating that neuronal energetics is supported by oxidative glucose metabolism. The 13 C NMR spectroscopy in combination with the infusion of 13 C labeled substrates could identify subtle perturbations in the cerebral function in different neurological diseases (Meisingset et al. 2010; Eyjolfsson et al. 2011; Tiwari and Patel 2012 "
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study, we have evaluated cerebral atrophy, neurometabolite homeostasis, and neural energetics in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) model of Parkinson's disease. In addition, the efficacy of acute l-DOPA treatment for the reversal of altered metabolic functions was also evaluated. Cerebral atrophy and neurochemical profile were monitored in vivo using MRI and 1H MR Spectroscopy. Cerebral energetics was studied by 1H-[13C]-NMR spectroscopy in conjunction with infusion of 13C labeled [1,6-13C2]glucose or [2-13C]acetate. MPTP treatment led to reduction in paw grip strength and increased level of GABA and myo-inositol in striatum and olfactory bulb. 13C Labeling of glutamate-C4 (1.93 ± 0.24 vs. 1.48 ± 0.06 μmol/g), GABA-C2 (0.24 ± 0.04 vs. 0.18 ± 0.02 μmol/g) and glutamaine-C4 (0.26 ± 0.04 vs. 0.20 ± 0.04 μmol/g) from [1,6-13C2]glucose was found to be decreased with MPTP exposure in striatum as well as in other brain regions. However, glutamine-C4 labeling from [2-13C]acetate was found to be increased in the striatum of the MPTP-treated mice. Acute l-DOPA treatment failed to normalize the increased ventricular size and level of metabolites but recovered the paw grip strength and 13C labeling of amino acids from [1,6-13C2]glucose and [2-13C]acetate in MPTP-treated mice. These data indicate that brain energy metabolism is impaired in Parkinson's disease and acute l-DOPA therapy could temporarily recover the cerebral metabolism. Cerebral atrophy, neurometabolite homeostasis, and neural energetics have been evaluated in an MPTP model of Parkinson's disease using MRI, in vivo 1H MRS and 1H-[13C]-NMR spectroscopy, respectively. MPTP treatment led to reduced paw grip strength and neuronal function. Acute Levodopa treatment was able to recover the diminished motor function and cerebral function. CMRGlc, Cerebral metabolic rate of glucose oxidation; MPTP, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridin.
    Journal of Neurochemistry 08/2013; 127(3). DOI:10.1111/jnc.12407 · 4.28 Impact Factor
Show more