Speaker: Dr.Pierre J. Magistretti
Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL) and Centre de Neurosciences Psychiatriques,
CHUV – Université de Lausanne
Lausanne, Switzerland

Host

Dr. Joan Guinovart

Friday, 13 June 2008, 12.00h Aula Fèlix Serratosa

Abstract

The coupling between synaptic activity and glucose utilization (neurometabolic coupling) is a central physiological principle of brain function which has provided the basis for 2-deoxyglucose-based functionalimaging with PET. About ten year ago we provided experimental evidence indicating a central role of astrocytes in neurometabolic coupling. The basic mechanism in neurometabolic coupling is the glutamate-stimulated aerobic glycolysis in astrocytes, such that the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na-K-ATPase triggers glucose uptake and its glycolytic processing, resulting in the release of lactate from astrocytes. Lactate can then contribute to the activity-dependent fuelling of the neuronal energy demands associated with synaptic transmission. Analyses of this coupling have been extended in vivo, and recently have also defined the modalities of coupling for inhibitory neurotransmission as w ell as its spatial extent in relation to the propagation of metabolic signals within the astrocytic syncytium .On the basis of a large body of experimental evidence w e have proposed an operational model, "the astrocyte-neuron lactate shuttle". Recently a series of results obtained by independent laboratories has provided further support for this model. This body of evidence provides a molecular and cellular basis for interpreting data obtained with functional brain imaging studies.

Pierre Magistretti’s interest in neuroenergetics began in the early 1980s w hen, on the basis of the demonstration of a glycogenolytic effect of VIP, he proposed an original hypothesis according to which certain neurotransmitters may have primarily a role in regulating brain homeostasis by acting on astrocytes. He contrasted the metabolic action of VIP, contained in locally-acting bipolar neurons and hence restricted to cortical columnar modules, to that of noradrenaline, which given the horizontal orientation of its fibers which span across functionally-distict cortical areas, would be in a position to prime metabolically the neocortex globally. Following on this line of research Pierre Magistretti described the existence of “metabolic hot-spots” in the neocortex as a result of the synergistic interaction between VIP and Noradrenaline at the levels of cortical columns. Later his laboratory described the molecular mechanisms that result in a transcriptionally-regulated massive stimulation of glycogen resynthesis in astrocytes. This process is mediated by cAMP-dependent mechanisms, involves the family of transcription factors C/EBP and results in the induction of Protein Targeting to Glycogen (PTG ) expression and of glycogen synthase activity. In addition, marked variations in the expression of genes involved in glial glycogen metabolism are observed during the sleep-wake cycle, with in particular a marked induction of expression of the gene encoding for PTG following sleep-deprivation. These data suggest that glial metabolic functions are subject to plasticity.

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