Hypoglutamatergic activity in the STOP knockout mouse: a potential model for chronic untreated schizophrenia.
In mice, the deletion of the STOP protein leads to hyperdopaminergia and major behavioral disorders that are alleviated by neuroleptics, representing a potential model of schizophrenia. The reduction of the glutamatergic synaptic vesicle pool in the hippocampus could reflect a disturbance in glutamatergic neurotransmission in this model. Here we examined potential disturbances in energy metabolism and interactions between neurons and glia in 15-week-old STOP KO, wild-type, and heterozygous mice. Animals received [1-(13)C]glucose and [1,2-(13)C]acetate, the preferential substrates of neurons and astrocytes, respectively. Extracts from the whole forebrain and midbrain were analyzed by HPLC, (13)C and (1)H NMR spectroscopy. Amounts and labeling of most metabolites were unchanged. However, glutamine concentration and amount of [4,5-(13)C]glutamine derived from [1,2-(13)C]acetate significantly decreased by 17% and 18%, respectively, in STOP KO compared with wild-type mice. The amount of [4-(13)C]glutamate was decreased in STOP KO and heterozygous compared with wild-type mice. gamma-Aminobutyric acid labeling was not influenced by the genotype. Because STOP-deficient mice have a lower synaptic vesicle density, less glutamate is released to the synaptic cleft, leading to decreased stimulation of the postsynaptic glutamate receptors, reflecting increased glutamine metabolism only in the vicinity of the postsynapse of STOP KO mice.
Brenner
Eiliv
E
Department of Neuroscience, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
Sonnewald
Ursula
U
Schweitzer
Annie
A
Andrieux
Annie
A
Nehlig
Astrid
A
D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry; D002851:Chromatography, High Pressure Liquid; D002908:Chronic Disease; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency; D004734:Energy Metabolism; D018698:Glutamic Acid / Q000172:deficiency*; D005973:Glutamine / Q000172:deficiency; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology*; D013572:Synaptic Vesicles / Q000378:metabolism
D008869:Microtubule-Associated Proteins; C491893:Mtap6 protein, mouse; D005973:Glutamine; D018698:Glutamic Acid; D004298:Dopamine