The Glutamine–Glutamate/GABA Cycle: Function, Regional Differences in Glutamate and GABA Production and Effects of Interference with GABA Metabolism

Abstract

The operation of a glutamine-glutamate/GABA cycle in the brain consisting of the transfer of glutamine from astrocytes to neurons and neurotransmitter glutamate or GABA from neurons to astrocytes is a well-known concept. In neurons, glutamine is not only used for energy production and protein synthesis, as in other cells, but is also an essential precursor for biosynthesis of amino acid neurotransmitters. An excellent tool for the study of glutamine transfer from astrocytes to neurons is [(14)C]acetate or [(13)C]acetate and the glial specific enzyme inhibitors, i.e. the glutamine synthetase inhibitor methionine sulfoximine and the tricarboxylic acid cycle (aconitase) inhibitors fluoro-acetate and -citrate. Acetate is metabolized exclusively by glial cells, and [(13)C]acetate is thus capable when used in combination with magnetic resonance spectroscopy or mass spectrometry, to provide information about glutamine transfer. The present review will give information about glutamine trafficking and the tools used to map it as exemplified by discussions of published work employing brain cell cultures as well as intact animals. It will be documented that considerably more glutamine is transferred from astrocytes to glutamatergic than to GABAergic neurons. However, glutamine does have an important role in GABAergic neurons despite their capability of re-utilizing their neurotransmitter by re-uptake.

Creatine, Glutamine plus Glutamate, and Macromolecules Are Decreased in the Central White Matter of Premature Neonates around Term

“…Glutamate is the most abundant aminoacid in the brain and the main excitatory neurotransmitter. It is involved in the glutamine-glutamate/GABA cycle between astrocytes and neurons [55]. Glutamate released by the synapse is taken up by astrocytes and converted to glutamine by glutamine synthetase.…”

“…Glutamate released by the synapse is taken up by astrocytes and converted to glutamine by glutamine synthetase. Glutamine may in turn be transferred to glutamatergic or GABAergic neurons to replenish their glutamate or GABA pools [55]. Glutamate and glutamine de novo synthesis and degradation are related to the tricarboxylic cycle, which produces energy in cells [55, 56].…”

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

“…In line with these findings, we have previously reported that the synthesis of neurotransmitter GABA is altered during chronic HE (Leke et al, 2011a), albeit no change was observed in the expression of GAD65, which is the GAD isoform closely associated with the biosynthesis of GABA in the vesicular neurotransmitter pool Waagepetersen et al, 1999Waagepetersen et al, , 2001Walls et al, 2011). Considering that glutamine is important in the restoration of GABA pools and that synthesis of this amino acid is disturbed during HE, it is possible that during this neurologic disorder the expression of the glutamine transporter isoforms might be altered which would consequently affect the function of the glutamate/GABA-glutamine cycle and thus likely contribute to the observed disturbance of GABA neurotransmitter synthesis (for further discussion, see Walls et al, 2015). …”

Effect of Interleukin-1Beta (IL-1<i>β</i>) on the Cortical Neurons Survival and Neurites Outgrowth

“…Astrocytes act also as important regulators of brain inflammation [3]. In addition, numerous studies have demonstrated the importance of astrocytes in a variety of neurophysiological processes such as the supply of energy metabolites, defense against oxidative stress or neurotransmitter reuptake and recycling [4]- [6].…”