KAUST Research Workshop on Innovative Technologies to Study Brain Energy Metabolism
King Abdullah University of Science & Technology, Saudi Arabia
Professor Magistretti has made significant contributions in the field of
brain energy metabolism. His group has discovered some of the cellular
and molecular mechanisms that underlie the coupling between neuronal
activity and energy consumption by the brain. This work has considerable
ramifications for the understanding of the origin of the signals
detected with the current functional brain imaging techniques used in
neurologic and psychiatric research.Magistretti’s research
interests include the cellular and molecular bases of brain energy
metabolism and brain imaging and the behavioral, cellular and molecular
determinants of neuronal and glial plasticity.
Professor Magistretti is Distinguished Professor of Bioscience
and Dean of the Biological and Environmental Science and Engineering Division at KAUST.
Pierre J. Magistretti, MD, PhDDivision of Biological and Environmental Sciences and Engineering, KAUST, Thuwal, KSA Brain Mind Institute, EPFL, Lausanne, SwitzerlandA tight metabolic coupling between astrocytes and neurons is a key feature of brain energy metabolism (Bélanger et al Cell Metab 2011; Magistretti and Allaman, Neuron 2015). Over the years we have described two basic mechanisms of neurometabolic coupling. First the glycogenolytic effect of VIP - restricted to cortical columns - and of noradrenaline - spanning across functionally distinct cortical areas - indicating a regulation of brain homeostasis by neurotransmitters acting on astrocytes, as glycogen is exclusively localized in these cells. Second, the glutamate-stimulated aerobic glycolysis in astrocytes. This metabolic response is mediated by the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na-K-ATPase. This results in the release of lactate from astrocytes, which can then fuel the neuronal energy demands a mechanisms known as the ANLS (for review see Pellerin and Magistretti JCBFM 2011). The ANLS model provides a direct mechanism to couple synaptic activity with glucose use and is consistent with the notion that the signals detected during physiological activation with 18F-deoxyglucose (DG)-PET may reflect predominantly uptake of the tracer into astrocytes. This conclusion does not question the validity of the 2-DG-based techniques, rather it provides a cellular and molecular basis for these functional brain imaging techniques.We have recently revealed a second function of lactate, as a signaling molecule for plasticity. Indeed we have shown that lactate derived from astrocytic glycogen is necessary for long-term memory consolidation and for induction in neurons of plasticity genes such as Arc and for maintenance of LTP (Suzuki et al, Cell 2011; for review see Magistretti and Allaman, Nature Reviews Neuroscience, 2018). We therefore set out to investigate the molecular mechanisms at the basis of the function of L-lactate on neuronal plasticity. We have found that L-lactate stimulates the expression of synaptic plasticity-related genes such as Arc, Zif268 and BDNF through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2 (Yang et al, PNAS 2014). L-lactate potentiates NMDA receptor-mediated currents and the ensuing increases in intracellular calcium. In parallel to this, L-lactate increases intracellular levels of NADH hence modulating the redox state of neurons. NADH mimicks all the effects of L-lactate on NMDA signaling, pointing to NADH increase as a primary mediator of L-lactate effects. Effects on plasticity gene expression are observed both in primary neurons in culture and in vivo in the sensory-motor cortex. These results provide novel insights for the understanding of the molecular mechanisms underlying the critical role of astrocyte-derived L-lactate in long term memory and reveal a novel action of L-lactate as a signaling molecule for neuronal plasticity.Using a fully immersive virtual reality (VR) environment (CAVE, caveautomatic virtual environment) in which 3D electron microscopy stacks were reconstructed and segmented for the different cellular and subcellular elements in the rat hippocamous, we observed a nonrandom distribution of glycogen granules, with a high enrichment around synaptic boutons (Cali et al J. Comp. Neurol. 2016).