Compartmentalised energy metabolism supporting glutamatergic neurotransmission in response to increased activity in the rat cerebral cortex: A ¹³C MRS study in vivo at 14.1 T

Abstract

Many tissues exhibit metabolic compartmentation. In the brain, while there is no doubt on the importance of functional compartmentation between neurons and glial cells, there is still debate on the specific regulation of pathways of energy metabolism at different activity levels. Using (13)C magnetic resonance spectroscopy (MRS) in vivo, we determined fluxes of energy metabolism in the rat cortex under α-chloralose anaesthesia at rest and during electrical stimulation of the paws. Compared to resting metabolism, the stimulated rat cortex exhibited increased glutamate-glutamine cycle (+67 nmol/g/min, +95%, P < 0.001) and tricarboxylic (TCA) cycle rate in both neurons (+62 nmol/g/min, +12%, P < 0.001) and astrocytes (+68 nmol/g/min, +22%, P = 0.072). A minor, non-significant modification of the flux through pyruvate carboxylase was observed during stimulation (+5 nmol/g/min, +8%). Altogether, this increase in metabolism amounted to a 15% (67 nmol/g/min, P < 0.001) increase in CMRglc(ox), i.e. the oxidative fraction of the cerebral metabolic rate of glucose. In conclusion, stimulation of the glutamate-glutamine cycle under α-chloralose anaesthesia is associated to similar enhancement of neuronal and glial oxidative metabolism.

How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo

“…Currently, the development of tracers detectable by MRS, such as 13 C-labeled substrates, the improvement of detection modalities (Henry et al, 2003), the progress in building adequate mathematical models (Gruetter et al, 2001) along with the increase in magnetic field strength render possible detailed compartmentalized metabolic flux characterization in vivo in a non-invasive manner and with minimal assumptions (Duarte et al, 2011; Duarte and Gruetter, 2013; Dehghani et al, 2016; Sonnay et al, 2016, 2017). In particular direct detection of 13 C-labeled compounds ( 13 C MRS) provides quantitative assessment of major metabolic pathways including glycolysis, TCA cycle, glutamate-glutamine cycle and pyruvate carboxylase (Gruetter et al, 2001; Henry et al, 2006; Duarte et al, 2011).…”

“…In addition, calculated fluxes are total glial TCA cycle activity (${\text{V}}_{\text{TCA}}^{\text{g}}$ = V g + V PC ), the glutamine synthetase rate (V GS = V NT + V PC ), the total cerebral metabolic rate of glucose oxidation (CMR glc(ox) = [${\text{V}}_{\text{TCA}}^{\text{n}}+$${\text{V}}_{\text{TCA}}^{\text{g}}+$V PC ]/2) and the pyruvate/lactate out-flux from the brain parenchyma (V out = 2CMR glc -2CMR glc(ox) + V in ). CMR glc is the cerebral metabolic rate of glucose and is usually determined together with the apparent maximum transport (T max ) and the apparent Michaelis constant of glucose transport K t using labeling of plasma and brain glucose (Duarte et al, 2011; Sonnay et al, 2016, 2017). In glial cells, GLS is neglected because the net 13 C labeling follows the direction of glutamine synthesis.…”

“…While the fate of neuronal ATP is likely involved in supporting other functions than the glutamate-glutamine cycle, such as stabilization of membrane potentials and restoration of ion (Na + , K + , and Ca 2+ ) gradients across the cell membrane (Attwell and Laughlin, 2001), the role of the considerable amount of ATP produced in glial cells (as estimated from recent 13 C MRS experiments in rodents; Duarte et al, 2011, 2015; Sonnay et al, 2016, 2017) is still unclear and likely extends beyond fueling glutamine synthetase, the Na + /K + -ATPase and the Ca 2+ -ATPase (Fresu et al, 1999). K + uptake has been recently suggested to fully account for astrocytic energy consumption (DiNuzzo et al, 2017).…”

Energy metabolism in the rat cortex under thiopental anaesthesia measured In Vivo by 13C MRS

“…Energy metabolism can be studied in the living brain using 13 C MRS during administration of 13 C‐enriched substrates (Henry et al, 2006). By measuring 13 C isotope incorporation over time into specific carbon positions of different molecules and by analysing these 13 C enrichments over time with appropriate mathematical models, one can determine the rate of oxidative metabolism in neurons and astrocytes, as well as the glutamate‐glutamine cycle rate (e.g., Gruetter et al, ; Duarte et al, ; Sonnay et al, ).…”

Editorial: In Vivo Magnetic Resonance at Ultra High Field

“…However, we expect to see this topic grow larger than it is because 13 C spectroscopy allows detection of many important organic compounds. Since the 90's, a few groups have performed 13 C experiments from 2.1 T to 14.1 T. One example of these efforts is to distinguish glutamate (Glu) and glutamine (Gln)in the brain [5,6]. As Glu-Gln cycling accounts for up to 80% of the energy consumption, it is essential in understanding the brain in the clinic or in the lab [7].…”