The overall goal of my group is to develop advanced magnetic resonance spectroscopy and imaging techniques and to apply them and other methods to studying brain metabolism and neurotransmission in both human subjects and in animal models. Magnetic resonance spectroscopy, in principle, allows measurement of neurotransmitter GABA, which plays an important role in many psychiatric diseases including depression and schizophrenia, and its metabolism. During 2004-2005, significant progress was made in the development of new spectroscopic techniques for single-voxel GABA measurement. In particular, we have developed a method which allows measuring the dynamic turnover of GABA from infused 13C-labeled glucose (11). It was found that the rate of label incorporation into GABA is significantly reduced upon inhibition of GABA transaminase. We are currently evaluating the rate of glutamine-GABA cycling flux and how it is modulated by the concentration of endogenous GABA. The effect of elevated GABA concentration on the glutamate-glutamine cycling flux is also being evaluated. This effort stemmed from our findings of the effect of antidepressant/antipanic drug phenelzine on the glutamate-glutamine cycling flux. By treating rats with phenelzine, the brain GABA was elevated while the rate of the glutamate-glutamine cycling flux was reduced (12). If proven to be a general effect, it will provide a mechanism of action for GABA-elevating drugs (8). Using our spectroscopy methods developed for the ultrahigh field strength of 11.7 Tesla, we have also evaluated brain energetics during functional activation. The phosphocreatine-to-creatine ratio was found to be significantly decreased in rat somatosensory cortex during forepaw stimulation, while no significant lactate elevation was detected. Our results indicate that increased energy consumption due to focal activation causes a shift in the creatine kinase reaction towards the direction of ATP production. At the same time, metabolic matching prevails during increased energy consumption with no significant increase in glycolysis (10). In addition to the above achievements, we have also developed a novel class of in vivo spectroscopy techniques, which allows the study of enzymology in vivo using 13C and possibly proton magnetic resonance spectroscopy. The first such experiment was performed for measuring the rate of the unidirectional glutamate to alpha-ketoglutarate flux in brain. The rate of this unidirectional flux, we hypothesize, should reflect the concentration of aspartate aminotransferase, which plays a key role in the metabolism of the major excitatory neurotransmitters glutamate and aspartate. By saturating the carbonyl carbons of their cognate keto acids, both the glutamate to alpha-ketoglutarate and the aspartate to oxaloacetate reactions were measured in vivo for the first time (9; J Shen, Theoretical analysis of carbon-13 magnetization transfer for in vivo exchange between alpha-ketoglutarate and glutamate, submitted to NMR Biomed.). We will further develop and refine the spectroscopy techniques for the in vivo measurement of aspartate aminotransferase reaction and characterize its role in brain function. Previous postmortem studies of brain disorders involving glutamatergic dysfunction have found that the activity of aspartate aminotransferase is significantly altered. Our new method will allow us to evaluate this enzyme in vivo.
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