Pears MR, Cooper JD, Mitchison HM, Mortishire-Smith RJ, Pearce DA, Griffin JL. High resolution 1H NMR-based metabolomics indicates a neurotransmitter cycling deficit in cerebral tissue from a mouse model of Batten disease. J Biol Chem 280: 42508-42514

Department of Biochemistry, Tennis Court Road, University of Cambridge, Cambridge CB2 1GA, United Kingdom.
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2006; 280(52):42508-14. DOI: 10.1074/jbc.M507380200
Source: PubMed


The neuronal ceroid lipofuscinoses (NCLs) constitute a range of progressive neurological disorders primarily affecting children.
Although six of the causative genes have been characterized, the underlying disease pathogenesis for this family of disorders
is unknown. Using a metabolomics approach based on high resolution 1H NMR spectroscopy of the cortex, cerebellum, and remaining regions of the brain in conjunction with statistical pattern recognition,
we report metabolic deficits associated with juvenile NCL in a Cln3 knock-out mouse model. Tissue from Cln3 null mutant mice aged 1–6 months was characterized by an increased glutamate concentration and a decrease in γ-amino butyric
acid (GABA) concentration in aqueous extracts from the three regions of the brain. These changes are consistent with the reported
altered expression of genes involved in glutamate metabolism in older mice and imply a change in neurotransmitter cycling
between glutamate/glutamine and the production of GABA. Further variations in myo-inositol, creatine, and N-acetyl-aspartate were also identified. These metabolic changes were distinct from the normal aging/developmental process.
Together, these changes represent the first documented pre-symptomatic symptoms of the Cln3 mouse at 1 month of age and demonstrate the versatility of 1H NMR spectroscopy as a tool for phenotyping mouse models of disease.

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    • "For example, 1 H-NMR has been used to uncover specific highly abundant metabolites (N-acetyl-aspartate, myo-inositol, glutamate , glutamine, creatine, choline, and GABA). Such studies have proven to be a key for the characterization of neurochemical and metabolic profiles relevant to brain health (Davidovic et al., 2011; Liu et al., 2013; Pears et al., 2005; Prabakaran et al., 2004; Tká c et al., 2004). Granting high reproducibility, the MR technologies are restricted by their low sensitivity, which hinders comprehensive pathologic assessments. "
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    ABSTRACT: Historically, studies of brain metabolism have been based on targeted analyses of a limited number of metabolites. Here we present an untargeted mass spectrometry-based metabolomic strategy that has successfully uncovered differences in a broad array of metabolites across anatomical regions of the mouse brain. The NSG immunodeficient mouse model was chosen because of its ability to undergo humanization leading to numerous applications in oncology and infectious disease research. Metabolic phenotyping by hydrophilic interaction liquid chromatography and nanostructure imaging mass spectrometry revealed both water-soluble and lipid metabolite patterns across brain regions. Neurochemical differences in metabolic phenotypes were mainly defined by various phospholipids and several intriguing metabolites including carnosine, cholesterol sulfate, lipoamino acids, uric acid, and sialic acid, whose physiological roles in brain metabolism are poorly understood. This study helps define regional homeostasis for the normal mouse brain to give context to the reaction to pathological events.
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    • "Specimens of bilateral brain hippocampus, NAc, PFC and striatum (~30-100 mg) were dissected immediately, snap-frozen in liquid nitrogen, and stored at -80°C until NMR spectroscopic analysis. The preparation of the brain samples was based on the previous studies [18,19]. The frozen tissue was added into 0.5 ml chloroform and homogenized at 4°C. "
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    ABSTRACT: Nicotine is rapidly absorbed from cigarette smoke and therefore induces a number of chronic illnesses with the widespread use of tobacco products. Studies have shown a few cerebral metabolites modified by nicotine; however, endogenous metabolic profiling in brain has not been well explored. H NMR-based on metabonomics was applied to investigate the endogenous metabolic profiling of brain hippocampus, nucleus acumens (NAc), prefrontal cortex (PFC) and striatum. We found that nicotine significantly increased CPP in mice, and some specific cerebral metabolites differentially changed in nicotine-treated mice. These modified metabolites included glutamate, acetylcholine, tryptamine, glucose, lactate, creatine, 3-hydroxybutyrate and nicotinamide-adenine dinucleotide (NAD), which was closely associated with neurotransmitter and energy source. Additionally, glutathione and taurine in hippocampus and striatum, phosphocholine in PFC and glycerol in NAc were significantly modified by nicotine, implying the dysregulation of anti-oxidative stress response and membrane metabolism. Nicotine induces significant metabonomic alterations in brain, which are involved in neurotransmitter disturbance, energy metabolism dysregulation, anti-oxidation and membrane function disruptions, as well as amino acid metabolism imbalance. These findings provide a new insight into rewarding effects of nicotine and the underlying mechanism.
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    • "quantitatively assay the entire range of metabolites present in a sample to characterize its overall biochemical state. Although MA sensitization has not yet been investigated using metabolomics, the platform has successfully identified biochemical signatures for other CNS pathologies including schizophrenia, Parkinson's and motor neuron disease (Bogdanov et al. 2008; Pears et al. 2005; Prabakaran et al. 2004). Thus, metabolomics offers the possibility of comprehensively mapping neurochemical profiles associated with MA-induced BSn, facilitating the identification of novel mechanisms , biomarkers and therapeutic targets. "
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    ABSTRACT: Behavioral sensitization has been widely studied in animal models and is theorized to reflect neural modifications associated with human psychostimulant addiction. While the mesolimbic dopaminergic pathway is known to play a role, the neurochemical mechanisms underlying behavioral sensitization remain incompletely understood. In the present study, we conducted the first metabolomics analysis to globally characterize neurochemical differences associated with behavioral sensitization. Methamphetamine-induced sensitization measures were generated by statistically modeling longitudinal activity data for eight inbred strains of mice. Subsequent to behavioral testing, nontargeted liquid and gas chromatography-mass spectrometry profiling was performed on 48 brain samples, yielding 301 metabolite levels per sample after quality control. Association testing between metabolite levels and three primary dimensions of behavioral sensitization (total distance, stereotypy and margin time) showed four robust, significant associations at a stringent metabolome-wide significance threshold (false discovery rate < 0.05). Results implicated homocarnosine, a dipeptide of GABA and histidine, in total distance sensitization, GABA metabolite 4-guanidinobutanoate and pantothenate in stereotypy sensitization, and myo-inositol in margin time sensitization. Secondary analyses indicated that these associations were independent of concurrent methamphetamine levels and, with the exception of the myo-inositol association, suggest a mechanism whereby strain-based genetic variation produces specific baseline neurochemical differences that substantially influence the magnitude of MA-induced sensitization. These findings demonstrate the utility of mouse metabolomics for identifying novel biomarkers, and developing more comprehensive neurochemical models, of psychostimulant sensitization.
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