Autism spectrum disorder (ASD) is a pervasive neurodevelopmental syndrome with a high human and economic burden. The pathophysiology of ASD is largely unclear, thus hampering development of pharmacological treatments for the core symptoms of the disorder. Abnormalities in glutamate and GABA signaling have been hypothesized to underlie ASD symptoms, and may form a therapeutic target, but it is not known whether these abnormalities are recapitulated in humans with ASD, as well as in rodent models of the disorder. We used translational proton magnetic resonance spectroscopy ([1H]MRS) to compare glutamate and GABA levels in adult humans with ASD and in a panel of six diverse rodent ASD models, encompassing genetic and environmental etiologies. [1H]MRS was performed in the striatum and the medial prefrontal cortex, of the humans, mice, and rats in order to allow for direct cross-species comparisons in specific cortical and subcortical brain regions implicated in ASD. In humans with ASD, glutamate concentration was reduced in the striatum and this was correlated with the severity of social symptoms. GABA levels were not altered in either brain region. The reduction in striatal glutamate was recapitulated in mice prenatally exposed to valproate, and in mice and rats carrying Nlgn3 mutations, but not in rodent ASD models with other etiologies. Our findings suggest that glutamate/GABA abnormalities in the corticostriatal circuitry may be a key pathological mechanism in ASD; and may be linked to alterations in the neuroligin–neurexin signaling complex.

The metabolism of [1,2-13C2]glucose and [U-13C4]3-hydroxybutyrate was studied in rat brain with in vivo and in vitro 13C NMR spectroscopy, taking advantage, in particular, of homonuclear 13C-13C spin coupling patterns. After infusion of [1,2-13C2]glucose or [U-13C4]3-hydroxybutyrate into rats, the uptake of the substrates in brain and their metabolism to [1-13C]bicarbonate could be detected with in vivo 13C NMR spectroscopy. At the end of the infusion experiment, methanol/HCl/HClO4 extracts of the brain tissue were further analysed by high resolution 13C NMR spectroscopy. The 13C spin coupling patterns revealed entirely different isotopomer distributions for the closely related cerebral metabolites glutamate, glutamine and 4-aminobutyric acid. A quantitative analysis of the 13C spectra demonstrated (i) the existence of two kinetically distinct pools of glutamate, (ii) a pronounced CO2 fixation via pyruvate carboxylase in the glial cells accounting for as much as 38% of the oxaloacetate synthesis in the glial tricarboxylic acid cycle, (iii) a cerebral pyruvate recycling system contributing maximally 17% of the pyruvate metabolism through the pyruvate dehydrogenase in neurons, and (iv) a predominant production of 4-aminobutyric acid from glutamate synthesized in the neurons. In addition, the labelling pattern of N-acetyl aspartate upon infusion of labelled glucose or 3-hydroxybutyrate provided insight into the synthesis of this compound in mammalian brain. While the acetyl moiety originates from the metabolic equivalent of the C-1-C-2 part of cerebral glutamate, the aspartyl moiety is not in direct contact with the intermediates of glycolysis or of the tricarboxylic acid cycles.

ObjectiveType 2 diabetes and obesity are emerging pandemics in the 21st century creating worldwide urgency for the development of novel and safe therapies. We investigated trace amine-associated receptor 1 (TAAR1) as a novel target contributing to the control of glucose homeostasis and body weight.MethodsWe investigated the peripheral human tissue distribution of TAAR1 by immunohistochemistry and tested the effect of a small molecule TAAR1 agonist on insulin secretion in vitro using INS1E cells and human islets and on glucose tolerance in C57Bl6, and db/db mice. Body weight effects were investigated in obese DIO mice.ResultsTAAR1 activation by a selective small molecule agonist increased glucose-dependent insulin secretion in INS1E cells and human islets and elevated plasma PYY and GLP-1 levels in mice. In diabetic db/db mice, the TAAR1 agonist normalized glucose excursion during an oral glucose tolerance test. Sub-chronic treatment of diet-induced obese (DIO) mice with the TAAR1 agonist resulted in reduced food intake and body weight. Furthermore insulin sensitivity was improved and plasma triglyceride levels and liver triglyceride content were lower than in controls.ConclusionsWe have identified TAAR1 as a novel integrator of metabolic control, which acts on gastrointestinal and pancreatic islet hormone secretion. Thus TAAR1 qualifies as a novel and promising target for the treatment of type 2 diabetes and obesity.

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Gastric emptying and gastrointestinal (GI) transit times in mice and humans were monitored noninvasively by using 27 Al and 19 F nuclear magnetic resonance (NMR). Al 3؉ bound to ion-exchange resin and perfluorononane were administered orally as selective and specific markers for the stomach and the entire GI tract, respectively.27 Al-and 19 F-MR spectroscopy (MRS) was employed to follow quantitatively boli of the mixed markers in awake, fed mice over a period of 48 hr. The selectivity of the markers was confirmed by whole-body 1 H-, 27 Al-, and 19 F-MRI of anesthetized mice. Gastric emptying in humans was also monitored with 27 Al-MRS of aluminum-loaded ion exchange resin. GI transit was assessed by 19 F projection imaging of pharmaceutical capsules tagged with perfluorononane. Quantitative analysis of the MR data revealed that gastric emptying in humans proceeded linearly, whereas in mice an exponential decay was observed. This difference is explained by the respective feeding patterns of humans and mice. Humans usually achieve nearly complete gastric emptying before each meal. In contrast, very short delays between successive food intakes in small animals result in successive dilution of the stomach contents. For stomach emptying in mice the exponential decay constant was 74 min, whereas the half-time of the linear gastric emptying in humans was 30 min.Magn Reson Med 48: 255-261, 2002.