Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity

Abstract

To determine the relationship between cerebral Glc metabolism and glutamatergic neuronal function, we used 13 C NMR spectroscopy to measure, simultaneously, the rates of the tricarboxylic acid cycle and Gln synthesis in the rat cortex in vivo. From these measurements, we calculated the rates of oxidative Glc metabolism and glutamate-neurotransmitter cycling between neurons and astrocytes (a quantitative measure of glutamatergic neuronal activity). By measuring the rates of the tricarboxylic acid cycle and Gln synthesis over a range of synaptic activity, we have determined the stoichiometry between oxidative Glc metabolism and glutamateneurotransmitter cycling in the cortex to be close to 1:1. This finding indicates that the majority of cortical energy production supports functional (synaptic) glutamatergic neuronal activity. Another implication of this result is that brain activation studies, which map cortical oxidative Glc metabolism, provide a quantitative measure of synaptic glutamate release.Glc metabolism is the major pathway of energy production in the mature brain (1). During brain activation, increases in Glc metabolism directly form the basis of brain functional mapping by using both 2-deoxyglucose autoradiography (2, 3) and positron-emission tomography (4) and indirectly influence signal changes observed with functional MRI (5). Despite the extensive use of these methods for mapping brain function, the mechanism linking Glc metabolism and functional neuronal activity and the fraction of cerebral energy production that supports neuronal function are still unknown.Glutamate is the major excitatory neurotransmitter in the brain (6), and a high percentage of cortical neurons are glutamatergic (7). It has been proposed that a neuronalastrocytic neurotransmitter cycle exists in the brain in which glutamate from the neuronal pool is released into the synaptic cleft as a neurotransmitter, taken up by astrocytes, converted to Gln, and returned to the neuron in this synaptically inactive form where it is converted back to glutamate (6). The development of in vivo 13 C NMR spectroscopy has enabled the direct investigation of cerebral glutamate metabolism (8, 9). We recently have shown that the rate of glutamateneurotransmitter cycling between neurons and astrocytes can be calculated by using the flux of the 13 C label from glutamate to Gln in the rat brain in vivo during a [1-13 C]Glc infusion (10). Thus, we can obtain an in vivo measure of glutamatergic neuronal activity. In the same experiment, the flux of the 13 C label from [1-13 C]Glc into glutamate yields a simultaneous in vivo measurement of the cerebral tricarboxylic acid (TCA) cycle rate, from which oxidative Glc consumption can be derived (11,12). Therefore, by using the combined measurement of these two fluxes, we can determine quantitatively the stoichiometry between cerebral Glc metabolism and glutamatergic-synaptic activity in vivo.In the present study, we have used direct 13 C NMR spectroscopy to determine the cerebral (primarily cortical)...

Comprehensive correlation between neuronal activity and spin-echo blood oxygenation level-dependent signals in the rat somatosensory cortex evoked by short electrical stimulations at various frequencies and currents

“…This is supported by the evidence that the local field-evoked potential is attenuated by blocking glutamate release during forepaw stimulation (Kida et al, 2001(Kida et al, , 2006. This decrease in field-evoked potential is linearly related with the decrease in the evoked CMRO 2 as well as BOLD signal and CBF (Kida et al, 2001(Kida et al, , 2006, consistent with the result that the activation-dependent release of glutamate and the glutamate-glutamine cycles require a proportionate oxidative energy consumption (Sibson et al, 1998). Furthermore, a linear relationship between BOLD signals and oxygen consumption associated with cortical activation produced by either physiological perturbations or forepaw stimulation has been reported (Kida et al, 2000;Sanganahalli et al, 2009;Herman et al, 2009).…”

Glutamatergic Function in the Resting Awake Human Brain is Supported by Uniformly High Oxidative Energy

“…4 But recent experimental studies in rodents and theoretical modeling have converged on the conclusion that majority of the resting energy consumption supports glutamatergic signaling and the energy demand changes linearly with pyramidal neuron firing rates and glutamate neurotransmitter release and reuptake. [5][6][7][8][9] Therefore in rodent models it is possible, to a first order, to show that the resting energy is primarily dedicated to total glutamatergic signaling, and the changes in neuronal signaling relative to a well-defined resting activity level can be used to calibrate changes in energy consumption during functional magnetic resonance imaging (fMRI) experiments. 10,11 In the awake human brain, however, the fraction of resting energy usage devoted to glutamatergic signaling is less well understood.…”

“…The magnitude of neuronal signaling in the human brain, and by inference the commensurate energy demand, underscores the functional relevance of resting activity and has profound implications for interpreting fMRI experiments in humans. [12][13][14] Given the rapidly increasing use of resting-state fMRI in mapping networks-defined as a subset of cortical and subcortical gray-matter regions that function together 15,16 -it is important to quantitatively establish if in the resting human the metabolic demand for neuronal signaling is high, as has been established for the rodent, 5,[7][8][9] and to what extent metabolic demand varies across gray-matter regions. 13 C magnetic resonance spectroscopy (MRS) of 13 C-labeled substrates (e.g., glucose and acetate) can measure rates of 13 C label incorporation into cell-specific pools (e.g., glutamate and gamino butyric acid (GABA) are predominantly neuronal and glutamine is predominantly glial) thereby estimating metabolic fluxes 17 of neuronal glucose oxidation (CMR glc(ox),N ) and of total glutamate neurotransmitter cycling (V cyc(tot) ).…”

The metabolomic profile during isoflurane anesthesia differs from propofol anesthesia in the live rodent brain

“…In line with 'a', the Glu-neurotransmitter cycling would also be expected to be reduced Figure 7 In the parietal cortex, the metabolomic analysis revealed a significant separation between the isoflurane-and propofolanesthetized animals, which was observed in the score plot (A -each blue diamond in the score plot represents a propofolanesthetized rat; and each of the black squares represents an isoflurane-anesthetized rat) with a cumulative Q 2 value of 0.70 on the combined first and second components, indicating an excellent fit of the data according to the classification and a model of high predictive power. (Sibson et al, 1998), and the observation that [glu] and [glc] were negatively correlated in the parietal cortex suggesting that higher Glu levels were present in animals with lower Glc content is in opposition to this notion (cf. Figure 4).…”