Abstract
Glutamine is an essential cerebral metabolite. Several critical brain processes are directly linked to glutamine, including ammonia homeostasis, energy metabolism and neurotransmitter recycling. Astrocytes synthesize and release large quantities of glutamine, which is taken up by neurons to replenish the glutamate and GABA neurotransmitter pools. Astrocyte glutamine hereby sustains the glutamate/GABA-glutamine cycle, synaptic transmission and general brain function. Cerebral glutamine homeostasis is linked to the metabolic coupling of neurons and astrocytes, and relies on multiple cellular processes, including TCA cycle function, synaptic transmission and neurotransmitter uptake. Dysregulations of processes related to glutamine homeostasis are associated with several neurological diseases and may mediate excitotoxicity and neurodegeneration. In particular, diminished astrocyte glutamine synthesis is a common neuropathological component, depriving neurons of an essential metabolic substrate and precursor for neurotransmitter synthesis, hereby leading to synaptic dysfunction. While astrocyte glutamine synthesis is quantitatively dominant in the brain, oligodendrocyte-derived glutamine may serve important functions in white matter structures. In this review, the crucial roles of glial glutamine homeostasis in the healthy and diseased brain are discussed. First, we provide an overview of cellular recycling, transport, synthesis and metabolism of glutamine in the brain. These cellular aspects are subsequently discussed in relation to pathological glutamine homeostasis of hepatic encephalopathy, epilepsy, Alzheimer’s disease, Huntington’s disease and amyotrophic lateral sclerosis. Further studies on the multifaceted roles of cerebral glutamine will not only increase our understanding of the metabolic collaboration between brain cells, but may also aid to reveal much needed therapeutic targets of several neurological pathologies.
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Abbreviations
- AAT:
-
Aspartate aminotransferase
- AD:
-
Alzheimer’s disease
- ALAT:
-
Alanine aminotransferase
- ALS:
-
Amyotrophic lateral sclerosis
- Aβ:
-
Amyloid-β
- CNS:
-
Central nervous system
- CSF:
-
Cerebrospinal fluid
- Cx43:
-
Connexin 43
- EAAT:
-
Excitatory amino acid transporter
- GABA:
-
γ-Aminobutyric acid
- GABA-T:
-
GABA transaminase
- GAD:
-
Glutamate decarboxylase
- GAT:
-
GABA transporter
- GDH:
-
Glutamate dehydrogenase
- GLAST:
-
Glutamate aspartate transporter 1
- GLT-1:
-
Glutamate transporter-1
- GS:
-
Glutamine synthetase
- HD:
-
Huntington’s disease
- HE:
-
Hepatic encephalopathy
- iPSC:
-
Induced pluripotent stem cell
- LAT:
-
L-type amino acid transporter
- MCFA:
-
Medium-chain fatty acid
- MCL:
-
Molecular carbon labeling
- mHtt:
-
Mutant huntingtin protein
- MPT:
-
Mitochondrial permeability transition
- MRS:
-
Magnetic resonance spectroscopy
- MSO:
-
L-methionine sulfoximine
- NFT:
-
Neurofibrillary tangle
- PAG:
-
Phosphate-activated glutaminase
- PC:
-
Pyruvate carboxylase
- ROS:
-
Reactive oxygen species
- SLC:
-
Solute carrier
- SNAT:
-
Sodium-coupled neutral amino acid transporter
- SOD1:
-
Superoxide dismutase 1
- SSADH:
-
Succinic semialdehyde dehydrogenase
- TCA:
-
Tricarboxylic acid (cycle)
- TLE:
-
Temporal lobe epilepsy
- WT:
-
Wild-type
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This work was supported by an SSADH Association Fellowship and a grant from the Hørslev Foundation (both awarded to JVA).
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Andersen, J.V., Schousboe, A. Glial Glutamine Homeostasis in Health and Disease. Neurochem Res 48, 1100–1128 (2023). https://doi.org/10.1007/s11064-022-03771-1
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DOI: https://doi.org/10.1007/s11064-022-03771-1