title: Differences in neurotransmitter synthesis and intermediary metabolism between glutamatergic and GABAergic neurons during 4 hours of middle cerebral artery occlusion in the rat: the role of astrocytes in neuronal survival.
abstract: Astrocytes are intimately involved in both glutamate and gamma-aminobutyric acid (GABA) synthesis, and ischemia-induced disruption of normal neuroastrocytic interactions may have important implications for neuronal survival. The effects of middle cerebral artery occlusion (MCAO) on neuronal and astrocytic intermediary metabolism were studied in rats 30, 60, 120, and 240 minutes after MCAO using in vivo injection of [1-13C]glucose and [1,2- 13C]acetate combined with ex vivo 13C magnetic resonance spectroscopy and high-performance liquid chromatography analysis of the ischemic core (lateral caudoputamen and lower parietal cortex) and penumbra (upper frontoparietal cortex). In the ischemic core, both neuronal and astrocytic metabolism were impaired from 30 minutes MCAO. There was a continuous loss of glutamate from glutamatergic neurons that was not replaced as neuronal glucose metabolism and use of astrocytic precursors gradually declined. In GABAergic neurons astrocytic precursors were not used in GABA synthesis at any time after MCAO, and neuronal glucose metabolism and GABA-shunt activity declined with time. No flux through the tricarboxylic acid cycle was found in GABAergic neurons at 240 minutes MCAO, indicating neuronal death. In the penumbra, the neurotransmitter pool of glutamate coming from astrocytic glutamine was preserved while neuronal metabolism progressively declined, implying that glutamine contributed significantly to glutamate excitotoxicity. In GABAergic neurons, astrocytic precursors were used to a limited extent during the initial 120 minutes, and tricarboxylic acid cycle activity was continued for 240 minutes. The present study showed the paradoxical role that astrocytes play in neuronal survival in ischemia, and changes in the use of astrocytic precursors appeared to contribute significantly to neuronal death, albeit through different mechanisms in glutamatergic and GABAergic neurons.
authors.affiliation: Departments of Clinical Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: A
authors.initials: A
authors.lastname: Håberg
authors.forename: H
authors.initials: H
authors.lastname: Qu
authors.forename: O
authors.initials: O
authors.lastname: Saether
authors.forename: G
authors.initials: G
authors.lastname: Unsgård
authors.forename: O
authors.initials: O
authors.lastname: Haraldseth
authors.forename: U
authors.initials: U
authors.lastname: Sonnewald
mesh_terms: D000106:Acetate-CoA Ligase / Q000493:pharmacokinetics; D000409:Alanine / Q000096:biosynthesis / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D001224:Aspartic Acid / Q000096:biosynthesis / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D001786:Blood Glucose; D002247:Carbon Isotopes; D002450:Cell Communication / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002952:Citric Acid Cycle / Q000502:physiology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005625:Frontal Lobe / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D005947:Glucose / Q000493:pharmacokinetics; D018698:Glutamic Acid / Q000096:biosynthesis* / Q000378:metabolism; D005973:Glutamine / Q000096:biosynthesis / Q000378:metabolism; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism*; D007530:Isoflurane / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D017072:Neostriatum / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010296:Parietal Lobe / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: D018685:Anesthetics, Inhalation; D001786:Blood Glucose; D002247:Carbon Isotopes; D005973:Glutamine; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D007530:Isoflurane; D000106:Acetate-CoA Ligase; D005947:Glucose; D000409:Alanine