Deciphering Neuron-Glia Compartmentalization in Cortical Energy Metabolism

Energy demand is an important constraint on neural signaling. Several methods have been proposed to assess the energy budget of the brain based on a bottom-up approach in which the energy demand of individual biophysical processes are first estimated independently and then summed up to compute the brain's total energy budget. Here, we address this question using a novel approach that makes use of published datasets that reported average cerebral glucose and oxygen utilization in humans and rodents during different activation states. Our approach allows us (1) to decipher neuron-glia compartmentalization in energy metabolism and (2) to compute a precise state-dependent energy budget for the brain. Under the assumption that the fraction of energy used for signaling is proportional to the cycling of neurotransmitters, we find that in the activated state, most of the energy (∼80%) is oxidatively produced and consumed by neurons to support neuron-to-neuron signaling. Glial cells, while only contributing for a small fraction to energy production (∼6%), actually take up a significant fraction of glucose (50% or more) from the blood and provide neurons with glucose-derived energy substrates. Our results suggest that glycolysis occurs for a significant part in astrocytes whereas most of the oxygen is utilized in neurons. As a consequence, a transfer of glucose-derived metabolites from glial cells to neurons has to take place. Furthermore, we find that the amplitude of this transfer is correlated to (1) the activity level of the brain; the larger the activity, the more metabolites are shuttled from glia to neurons and (2) the oxidative activity in astrocytes; with higher glial pyruvate metabolism, less metabolites are shuttled from glia to neurons. While some of the details of a bottom-up biophysical approach have to be simplified, our method allows for a straightforward assessment of the brain's energy budget from macroscopic measurements with minimal underlying assumptions

Synaptic Plasticity and the Warburg Effect

Functional brain imaging studies show that in certain brain regions glucose utilization exceeds oxygen consumption, indicating the predominance of aerobic glycolysis. In this issue, Goyal et al. (2014) report that this metabolic profile is associated with an enrichment in the expression of genes involved in synaptic plasticity and remodeling processes

The role of astroglia in neuroprotection

Astrocytes are the main neural cell type responsible for the maintenance of brain homeostasis. They form highly organized anatomical domains that are interconnected into extensive networks. These features, along with the expression of a wide array of receptors, transporters, and ion channels, ideally position them to sense and dynamically modulate neuronal activity. Astrocytes cooperate with neurons on several levels, including neurotransmitter trafficking and recycling, ion homeostasis, energy metabolism, and defense against oxidative stress. The critical dependence of neurons upon their constant support confers astrocytes with intrinsic neuroprotective properties which are discussed here. Conversely, pathogenic stimuli may disturb astrocytic function, thus compromising neuronal functionality and viability. Using neuroinflammation, Alzheimer's disease, and hepatic encephalopathy as examples, we discuss how astrocytic defense mechanisms may be overwhelmed in pathological conditions, contributing to disease progression

Cellular Bases of Brain Energy Metabolism and Their Relevance to Functional Brain Imaging: Evidence for a Prominent Role of Astrocytes

Survey of Brain Energy Metabolism at the Organ and Regional Level

Selective Postsynaptic Co-localization of MCT2 with AMPA Receptor GluR2/3 Subunits at Excitatory Synapses Exhibiting AMPA Receptor Trafficking

MCT2 is the main neuronal monocarboxylate transporter needed by neurons if they are to use lactate as an additional energy substrate. Previous evidence suggested that some MCT2 could be located in postsynaptic elements of glutamatergic synapses. Using post-embedding electron microscopic immunocytochemistry, it is demonstrated that MCT2 is present at postsynaptic density of asymmetric synapses, in the stratum radiatum of both rat hippocampal CA1 and CA3 regions, as well as at parallel fibre-Purkinje cell synapses in mouse cerebellum. MCT2 levels were significantly lower at mossy fibre synapses on CA3 neurons, and MCT2 was almost absent from symmetric synapses on CA1 pyramidal cells. It could also be demonstrated using quantitative double-labeling immunogold cytochemistry that MCT2 and AMPA receptor GluR2/3 subunits have a similar postsynaptic distribution at asymmetric synapses with high levels expressed within the postsynaptic density. In addition, as for AMPA receptors, a significant proportion of MCT2 is located on vesicular membranes within the postsynaptic spine, forming an intracellular pool available for a putative postsynaptic endo/exocytotic trafficking at these excitatory synapses. Altogether, the data presented provide evidence for MCT2 expression in the postsynaptic density area at specific subsets of glutamatergic synapses, and also suggest that MCT2, like AMPA receptors, could undergo membrane traffickin

Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect

Epidemiological and biochemical studies show that the sporadic forms of Alzheimer's disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events—mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model

L-Lactate Regulates the Expression of Synaptic Plasticity and Neuroprotection Genes in Cortical Neurons: A Transcriptome Analysis

Lactate, a product of aerobic glycolysis in astrocytes, is required for memory formation and consolidation, and has recently emerged as a signaling molecule for neurons and various cell types in peripheral tissues. In particular lactate stimulates mRNA expression of a few plasticity-related genes. Here, we describe a RNA-seq study that unravels genome-wide transcriptomic responses to this energy metabolite in cortical neurons. Our results show that mRNA expression of 20 immediate-early genes involved in the MAPK signaling pathway and in synaptic plasticity were increased by more than twofold following 1 h of lactate stimulation. This effect was dependent on NMDA receptor (NMDAR) activity since it was prevented by pre-treatment with MK-801. Comparison with published datasets showed that a significant proportion of genes modulated by lactate were similarly regulated by a stimulation protocol activating specifically synaptic NMDARs known to result in upregulation of pro-survival and downregulation of pro-death genes. Remarkably, transcriptional responses to lactate were reproduced by NADH (for 74 of the 113 genes, FDR < 0.05), suggesting a redox-dependent mechanism of action. Longer-term gene expression changes observed after 6 h of lactate treatment affected genes involved in regulating neuronal excitability and genes coding for proteins localized at synapses. Gene set enrichment analyses performed with ranked lists of expressed genes revealed effects on molecular functions involved in epigenetic modulation, and on processes relevant to sleep physiology and behavioral phenotypes such as anxiety and hyperactivity. Overall, these results strengthen the notion that lactate effectively regulates activity-dependent and synaptic genes, and highlight new signaling effects of lactate in plasticity and neuroprotection

Extended preclinical investigation of lactate for neuroprotection after ischemic stroke

Lactate has been shown to have beneficial effect both in experimental ischemia–reperfusion models and in human acute brain injury patients. To further investigate lactate’s neuroprotective action in experimental in vivo ischemic stroke models prior to its use in clinics, we tested (1) the outcome of lactate administration on permanent ischemia and (2) its compatibility with the only currently approved drug for the treatment of acute ischemic stroke, recombinant tissue plasminogen activator (rtPA), after ischemia–reperfusion. We intravenously injected mice with 1 µmol/g sodium l -lactate 1 h or 3 h after permanent middle cerebral artery occlusion (MCAO) and looked at its effect 24 h later. We show a beneficial effect of lactate when administered 1 h after ischemia onset, reducing the lesion size and improving neurological outcome. The weaker effect observed at 3 h could be due to differences in the metabolic profiles related to damage progression. Next, we administered 0.9 mg/kg of intravenous (iv) rtPA, followed by intracerebroventricular injection of 2 µL of 100 mmol/L sodium l -lactate to treat mice subjected to 35-min transient MCAO and compared the outcome (lesion size and behavior) of the combined treatment with that of single treatments. The administration of lactate after rtPA has positive influence on the functional outcome and attenuates the deleterious effects of rtPA, although not as strongly as lactate administered alone. The present work gives a lead for patient selection in future clinical studies of treatment with inexpensive and commonly available lactate in acute ischemic stroke, namely patients not treated with rtPA but mechanical thrombectomy alone or patients without recanalization therapy