Glial‐Neuronal Interactions as Studied by Cerebral Metabolism of [2‐¹³C]Acetate and [1‐¹³C]Glucose: An Ex Vivo ¹³C NMR Spectroscopic Study

Abstract

Mice were injected intravenously with [2‐13C]‐acetate or [1‐13C]glucose and killed after 5, 15, or 30 min. Another group of animals was injected three times subcutaneously during 30 min with [2‐13C]acetate to achieve a steady‐state‐like situation. Brain extracts were analyzed by 13C NMR spectroscopy, and the percent enrichment of various carbon positions was calculated for amino acids, lactate, and glucose. Results obtained with [2‐13C]acetate, which is metabolized by glia and not by neurons, showed that glutamine originated from a glial tricarboxylic acid cycle (TCA cycle) that loses 65% of its intermediates per turn of the cycle. This TCA cycle was associated with pyruvate carboxylation, which may replenish virtually all of this loss, as seen from the labeling of glutamine from [1‐13C]glucose. From the C‐3/C‐4 labeling ratios in glutamine and glutamate and from the corresponding C‐3/C‐2 labeling ratio in GABA obtained with [2‐13C]acetate, it was concluded that the carbon skeleton of glutamine to some extent was passed through TCA cycles before glutamate and GABA were formed. Thus, astrocytically derived glutamine is not only a precursor for transmitter amino acids but is also an energy substrate for neurons in vivo. Furthermore, the neuronal TCA cycles may be control points in the synthesis of transmitter amino acids. Injection of [2‐13C]acetate led to a higher 13C enrichment of the C‐2 in glutamate and of the corresponding C‐4 in GABA than in the C‐3 of either compound. This could reflect cleavage of [2‐13C]‐citrate and formation of [3‐13C]oxaloacetate and acetyl‐CoA, i.e., the first step in fatty acid synthesis. [3‐13C]‐Oxaloacetate would, after entry into a TCA cycle, give the observed labeling of glutamate and GABA.

Astrocytic Function Assessed from 1-14C-Acetate Metabolism after Temporary Focal Cerebral Ischemia in Rats

“…As expected from previous studies of the metabolism of 1-14 C-acetate (Berl and Frigyesi, 1969;Haberg et al, 2001;Hassel et al, 1995), 14 C-radiolabel was also incorporated into glutamate, but at a lower specific activity than glutamine. The initial production of 14 C-glutamate from 14 C-acetate is also predominantly astrocytic based on the substantial impairment produced by the selective glial aconitase inhibitor, fluorocitrate (Fonnum et al, 1997).…”

Glutamate Metabolism is Impaired in Transgenic Mice with Tau Hyperphosphorylation

“…bolus injection of glucose, the concentration of glucose in the brain was not affected. 22 Thus, 13 C labeling in metabolites reported here reflects 13 C enrichment in brain and not blood glucose. In the present study, we found a decreased glutamate level in hippocampus whereas in cortex, glucose utilization and turnover of glutamate, glutamine, and GABA were increased.…”

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

“…Therefore, NAA can supply both acetate and oxaloacetate to the TCA cycle for energy production (Nadler and Cooper, 1972a), at least in oligodendrocytes where ASPA is present. Glial cells preferentially utilize acetate for energy production through the TCA cycle, as opposed to neurons (Bluml et al, 2002;Hassel et al, 1995;Muir et al, 1986) suggesting that oligodendrocytes could make substantial use of NAA-derived acetate for energy production when myelination is complete. It has also been proposed that NAA could act as a reservoir of glutamate in the brain, wherein NAA is converted to aspartate in oligodendrocytes, which could then be converted to glutamate through the TCA cycle with favorable energetics (Clark et al, 2006).…”