Astrocytic energy metabolism and glutamate formation--relevance for 13C-NMR spectroscopy and importance of cytosolic/mitochondrial trafficking

Glutamate plays a double role in ¹³C-nuclear magnetic resonance (NMR) spectroscopic determination of glucose metabolism in the brain. Bidirectional exchange between initially unlabeled glutamate and labeled α-ketoglutarate, formed from pyruvate via pyruvate dehydrogenase (PDH), indicates the rate of energy metabolism in the tricarboxylic acid (V_TCA) cycle in neurons (V_{PDH, n}) and, with additional computation, also in astrocytes (V_{PDH, g}), as confirmed using the astrocyte-specific substrate ¹³C]acetate. Formation of new molecules of glutamate during increased glutamatergic activity occurs only in astrocytes by combined pyruvate carboxylase (V_PC) and astrocytic PDH activity. V_{PDH, g} accounts for ∼15% of total pyruvate metabolism in the brain cortex, and V_PC accounts for another ∼10%. Since both PDH-generated and PC-generated pyruvates are needed for glutamate synthesis, ∼20/25 (80%) of astrocytic pyruvate metabolism proceed via glutamate formation. Net transmitter glutamate γ-aminobutyric acid (GABA)] formation requires transfer of newly synthesized α-ketoglutarate to the astrocytic cytosol, α-ketoglutarate transamination to glutamate, amidation to glutamine, glutamine transfer to neurons, its hydrolysis to glutamate and glutamate release (or GABA formation). Glutamate-glutamine cycling, measured as glutamine synthesis rate (V_cycle), also transfers previously released glutamate/GABA to neurons after an initial astrocytic accumulation and measures predominantly glutamate signaling. An empirically established ∼1/1 ratio between glucose metabolism and V_cycle may reflect glucose utilization associated with oxidation/reduction processes during glutamate production, which together with associated transamination processes are balanced by subsequent glutamate oxidation after cessation of increased signaling activity. Astrocytic glutamate formation and subsequent oxidative metabolism provide large amounts of adenosine triphosphate used for accumulation from extracellular clefts of neuronally released K⁺ and glutamate and for cytosolic Ca²⁺ homeostasis.