Differential distribution of the enzymes glutamate dehydrogenase and aspartate aminotransferase in cortical synaptic mitochondria contributes to metabolic compartmentation in cortical synaptic terminals

McKenna, Mary C.; Stevenson, Joseph; Huang, Xeuli; Hopkins, Irene B.

doi:10.1016/s0197-0186(00)00042-5

Cited by 136 publications

(128 citation statements)

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“…Neurons contain multiple "pools" of both glutamate and GABA. The largest pool is the "metabolic pool," which is approximately 1,000-fold higher than the synaptic pool, and is thought to be insular from the synaptic pool (23). However, because of greatly increased energy demand (24)(25)(26), released glutamate could be catabolized in the astrocyte for entry into the TCA cycle.…”

Section: Discussionmentioning

confidence: 99%

Dietary branched chain amino acids ameliorate injury-induced cognitive impairment

Cole¹,

Mitala²,

Kundu³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

130

139

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Neurological dysfunction caused by traumatic brain injury results in profound changes in net synaptic efficacy, leading to impaired cognition. Because excitability is directly controlled by the balance of excitatory and inhibitory activity, underlying mechanisms causing these changes were investigated using lateral fluid percussion brain injury in mice. Although injury-induced shifts in net synaptic efficacy were not accompanied by changes in hippocampal glutamate and GABA levels, significant reductions were seen in the concentration of branched chain amino acids (BCAAs), which are key precursors to de novo glutamate synthesis. Dietary consumption of BCAAs restored hippocampal BCAA concentrations to normal, reversed injury-induced shifts in net synaptic efficacy, and led to reinstatement of cognitive performance after concussive brain injury. All brain-injured mice that consumed BCAAs demonstrated cognitive improvement with a simultaneous restoration in net synaptic efficacy. Posttraumatic changes in the expression of cytosolic branched chain aminotransferase, branched chain ketoacid dehydrogenase, glutamate dehydrogenase, and glutamic acid decarboxylase support a perturbation of BCAA and neurotransmitter metabolism. Ex vivo application of BCAAs to hippocampal slices from injured animals restored posttraumatic regional shifts in net synaptic efficacy as measured by field excitatory postsynaptic potentials. These results suggest that dietary BCAA intervention could promote cognitive improvement by restoring hippocampal function after a traumatic brain injury.

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Section: Discussionmentioning

confidence: 99%

Dietary branched chain amino acids ameliorate injury-induced cognitive impairment

Cole¹,

Mitala²,

Kundu³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

130

139

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“…However, neither Asp nor GSH significantly changed in our study. Therefore, the Glu change observed was likely generated by increased flux through pyruvate carboxylase (Oz et al, 2004) and via glutamate dehydrogenase (McKenna et al, 2000) (Fig. 4B).…”

Section: Discussionmentioning

confidence: 99%

Are glutamate and lactate increases ubiquitous to physiological activation? A 1H functional MR spectroscopy study during motor activation in human brain at 7Tesla

Xin²,

et al. 2014

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a b s t r a c t a r t i c l e i n f oRecent studies at high field (7 Tesla) have reported small metabolite changes, in particular lactate and glutamate (below 0.3 μmol/g) during visual stimulation. These studies have been limited to the visual cortex because of its high energy metabolism and good magnetic resonance spectroscopy (MRS) sensitivity using surface coil. The aim of this study was to extend functional MRS (fMRS) to investigate for the first time the metabolite changes during motor activation at 7 T. Small but sustained increases in lactate (0.17 μmol/g ± 0.05 μmol/g, p b 0.001) and glutamate (0.17 μmol/g ± 0.09 μmol/g, p b 0.005) were detected during motor activation followed by a return to the baseline after the end of activation. The present study demonstrates that increases in lactate and glutamate during motor stimulation are small, but similar to those observed during visual stimulation. From the observed glutamate and lactate increase, we inferred that these metabolite changes may be a general manifestation of the increased neuronal activity. In addition, we propose that the measured metabolite concentration increases imply an increase in ΔCMR O2 that is transiently below that of ΔCMR Glc during the first 1 to 2 min of the stimulation.© 2014 Elsevier Inc. All rights reserved. IntroductionFunctional MR spectroscopy (fMRS) provides direct insights into brain metabolism by investigating the metabolic response of the brain to a physiological stimulus. The high spectral resolution and signal-tonoise ratio (SNR) of fMRS at high field (N3 Tesla) improve the accuracy and precision of the quantification of many brain metabolites (Mekle et al., 2009;Tkac et al., 2001Tkac et al., , 2009. In addition to the increased chemical shift dispersion, a high time resolution is of advantage for the characterization of the small transient changes observed. Recent fMRS studies (Lin et al., 2012;Mangia et al., 2007b;Schaller et al., 2013) at high field (7 Tesla) reported small metabolite concentration changes during visual stimulation (around 0.2 μmol/g). In particular, a very small lactate concentration increase between 10 and 23% has been observed. Recently, functional diffusion-weighted MRS has been used to investigate metabolite ADC changes as a potential consequence of micro structural changes during activation (Branzoli et al., 2013).The lactate increase observed during visual stimulation has been suggested to explain the mismatch of cerebral metabolic rate of change for glucose (ΔCMR Glc ) (or cerebral blood flow, CBF) and cerebral metabolic rate of change for oxygen (ΔCMR O2 ) during brain activation. However, many studies have reported different results concerning the transient mismatch of ΔCMR Glc , CBF and ΔCMR O2 during functional activity (reviewed in Buxton (2010)). The characterization of these changes has been reported in positron emission tomography (PET) (Fox and

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“…Glutamate dehydrogenase is present in neurons and glia (McKenna et al, 2000), and catalyzes the deamination of glutamate to alpha-ketoglutarate and ammonia using either NAD or NADP as cofactors (Mastorodemos et al, 2005). It is possible that neuronal mitochondria preferentially use the aspartate aminotransferase reaction instead of the glutamate dehydrogenase reaction to generate the key metabolite alpha ketoglutarate in order to avoid the problem of ammonia toxicity (Madhavarao et al, 2003;Madhavarao et al, 2005;Madhavarao and Namboodiri, 2006).…”

Section: A Model Of Naa Synthesis Linked To Mitochondrial Energetics mentioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,208

1,126

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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Differential distribution of the enzymes glutamate dehydrogenase and aspartate aminotransferase in cortical synaptic mitochondria contributes to metabolic compartmentation in cortical synaptic terminals

Cited by 136 publications

References 84 publications

Dietary branched chain amino acids ameliorate injury-induced cognitive impairment

Dietary branched chain amino acids ameliorate injury-induced cognitive impairment

Are glutamate and lactate increases ubiquitous to physiological activation? A 1H functional MR spectroscopy study during motor activation in human brain at 7Tesla

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

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