Neuroglial metabolism in the awake rat brain: CO₂ fixation increases with brain activity

Glial cells are thought to supply energy for neurotransmission by increasing nonoxidative glycolysis; however, oxidative metabolism in glia may also contribute to increased brain activity. To study glial contribution to cerebral energy metabolism in the unanesthetized state, we measured neuronal and glial metabolic fluxes in the awake rat brain by using a double isotopic-labeling technique and a two-compartment mathematical model of neurotransmitter metabolism. Rats (n = 23) were infused simultaneously with ¹⁴C-bicarbonate and [1-¹³C]glucose for up to 1 hr. The ¹⁴C and ¹³C labeling of glutamate, glutamine, and aspartate was measured at five time points in tissue extracts using scintillation counting and ¹³C nuclear magnetic resonance of the chromatographically separated amino acids. The isotopic ¹³C enrichment of glutamate and glutamine was different, suggesting significant rates of glial metabolism compared with the glutamate-glutamine cycle. Modeling the ¹³C-labeling time courses alone and with ¹⁴C confirmed significant glial TCA cycle activity (V_PDH^(g) ∼0.5 μmol · gm^-1 · min^-1) relative to the glutamate-glutamine cycle (V_NT) (∼0.5-0.6 μmol · gm^-1 · min^-1). The glial TCA cycle rate was ∼30% of total TCA cycle activity. A high pyruvate carboxylase rate (V _PC, ∼0.14-0.18 μmol · gm^-1 · min ^-1) contributed to the glial TCA cycle flux. This anaplerotic rate in the awake rat brain was severalfold higher than under deep pentobarbital anesthesia, measured previously in our laboratory using the same ¹³C-labeling technique. We postulate that the high rate of anaplerosis in awake brain is linked to brain activity by maintaining glial glutamine concentrations during increased neurotransmission.