Brain Slices from Glutaminase-Deficient Mice Metabolize Less Glutamine: A Cellular Metabolomic Study with Carbon 13 NMR

Hage, Mirella; Masson, Justine; Conjard-Duplany, Agnès; Ferrier, Bernard; Baverel, Gabriel; Martin, G.

doi:10.1038/jcbfm.2012.22

Cited by 15 publications

(12 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reduction in PAG activity of about 20% seen in stopGLS1 HET brain slices ( El Hage et al, 2012 ) is associated with about a 15% reduction in GLU content ( Gaisler-Salomon et al, 2009b ) that presumably reflects a presynaptic diminution, since the highest concentrations of GLU are intracellular ( Danbolt, 2001 ). Decreases in presynaptic GLU lead to decreases in vesicular GLU content and synaptic efficacy ( Ishikawa et al, 2002 ).…”

Section: Discussionmentioning

confidence: 99%

Dopamine neuron dependent behaviors mediated by glutamate cotransmission

Mingote

Chuhma

Kalmbach

et al. 2017

eLife

View full text Add to dashboard Cite

Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene Gls1). In mice with a dopamine transporter (Slc6a3)-driven conditional heterozygous (cHET) reduction of Gls1 in their dopamine neurons, dopamine neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling a selective focus on the cotransmission. The mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic neurons. Thus, a reduction in dopamine neuron glutamate cotransmission appears to mediate significant components of the GLS1 HET schizophrenia resilience phenotype, and glutamate cotransmission appears to be important in attribution of motivational salience.DOI: http://dx.doi.org/10.7554/eLife.27566.001

show abstract

Section: Discussionmentioning

confidence: 99%

Dopamine neuron dependent behaviors mediated by glutamate cotransmission

Mingote

Chuhma

Kalmbach

et al. 2017

eLife

View full text Add to dashboard Cite

show abstract

“…Rather, ex vivo activity reflects the amount of glutaminase protein present, reported by its maximal activity. Evaluating glutaminase inhibition in vivo requires tracking 13 C-precursor flux through astrocytes to neurons and the conversion of glutamine to glutamate by magnetic resonance spectroscopy (Patel et al, 2010 ; El Hage et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice

Mingote

Masson

Gellman

et al. 2016

Front. Syst. Neurosci.

Self Cite

View full text Add to dashboard Cite

Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAGERT2cre∕+ mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction—mimicking pharmacological inhibition—strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel target for the pharmacotherapy of schizophrenia. These results demonstrate how genetic pharmacotherapy can be implemented to test a CNS target in advance of the development of specific neuroactive inhibitors. We discuss further the advantages, limitations, and feasibility of the wider application of genetic pharmacotherapy for neuropsychiatric drug development.

show abstract

“…L-Aspartic acid also functions as a neurotransmitter. D-Glutamine forms part of the D-glutamate metabolic pathway and is converted from glutamate by astrocytes in the brain [45]. Glutamate, as an excitatory neurotransmitter, is released decarboxylated by neurons to yield the inhibitory neurotransmitter gammaaminobutyric acid (GABA) [46].…”

mentioning

confidence: 99%

Integrated Metabolomic and Lipidomic Analysis Reveals the Neuroprotective Mechanisms of Bushen Tiansui Formula in an Aβ1-42-Induced Rat Model of Alzheimer’s Disease

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Bushen Tiansui Formula (BSTSF) is a traditional Chinese medicine prescription. It has been widely applied to treat Alzheimer’s disease (AD) in the clinic; however, the mechanisms underlying its effects remain largely unknown. In this study, we used a rat AD model to study the effects of BSTSF on cognitive performance, and UPLC-MS/MS-based metabolomic and lipidomic analysis was further performed to identify significantly altered metabolites in the cerebral cortices of AD rats and determine the effects of BSTSF on the metabolomic and lipidomic profiles in the cerebral cortices of these animals. The results revealed that the levels of 47 metabolites and 30 lipids primarily associated with sphingolipid metabolism, glycerophospholipid metabolism, and linoleic acid metabolism were significantly changed in the cerebral cortices of AD rats. Among the altered lipids, ceramides, phosphatidylethanolamines, lysophosphatidylethanolamines, phosphatidylcholines, lysophosphatidylcholines, phosphatidylserines, sphingomyelins, and phosphatidylglycerols showed robust changes. Moreover, 34 differential endogenous metabolites and 21 lipids, of which the levels were mostly improved in the BSTSF treatment group, were identified as potential therapeutic targets of BSTSF against AD. Our results suggest that lipid metabolism is highly dysregulated in the cerebral cortices of AD rats, and BSTSF may exert its neuroprotective mechanisms by restoring metabolic balance, including that of sphingolipid metabolism, glycerophospholipid metabolism, alanine, aspartate, and glutamate metabolism, and D-glutamine and D-glutamate metabolism. Our data may lead to a deeper understanding of the AD-associated metabolic profile and shed new light on the mechanism underlying the therapeutic effects of BSTSF.

show abstract

Brain Slices from Glutaminase-Deficient Mice Metabolize Less Glutamine: A Cellular Metabolomic Study with Carbon 13 NMR

Cited by 15 publications

References 32 publications

Dopamine neuron dependent behaviors mediated by glutamate cotransmission

Dopamine neuron dependent behaviors mediated by glutamate cotransmission

Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice

Integrated Metabolomic and Lipidomic Analysis Reveals the Neuroprotective Mechanisms of Bushen Tiansui Formula in an Aβ1-42-Induced Rat Model of Alzheimer’s Disease

Contact Info

Product

Resources

About