Challenges of Investigating Compartmentalized Brain Energy Metabolism Using Nuclear Magnetic Resonance Spectroscopy in vivo

Brain function requires continuous energy supply. Thus, unraveling brain metabolic regulation is critical not only for our basic understanding of overall brain function, but also for the cellular basis of functional neuroimaging techniques. While it is known that brain energy metabolism is exquisitely compartmentalized between astrocytes and neurons, the metabolic and neuro-energetic basis of brain activity is far from fully understood. ¹H nuclear magnetic resonance (NMR) spectroscopy has been widely used to detect variations in metabolite levels, including glutamate and GABA, while ¹³C NMR spectroscopy has been employed to study metabolic compartmentation and to determine metabolic rates coupled brain activity, focusing mainly on the component corresponding to excitatory glutamatergic neurotransmission. The rates of oxidative metabolism in neurons and astrocytes are both associated with the rate of the glutamate-glutamine cycle between neurons and astrocytes. However, any possible correlation between energy metabolism pathways and the inhibitory GABAergic neurotransmission rate in the living brain remains to be experimentally demonstrated. That is due to low GABA levels, and the consequent challenge of determining GABAergic rates in a non-invasive manner. This brief review surveys the state-of-the-art analyses of energy metabolism in neurons and astrocytes contributing to glutamate and GABA synthesis using ¹³C NMR spectroscopy in vivo, and identifies limitations that need to be overcome in future studies.