Group leader: Gilles Bonvento
Metabolic Interactions between Neurons and Astrocytes
In brief
The learning of new information and the short- and long-term storage of these acquisitions require a cascade of events that are energy-intensive for brain cells. In addition to neurons, astrocytes coordinate the molecular mechanisms regulating learning, memory and energy metabolism (Bolanos and Bonvento, Cell Metabolism 2021). The team’s project aims to study the interactions between the metabolic and signaling properties of astrocytes, and how these two properties integrate to enable cognitive tasks. The medium-term objective is to determine whether and how alterations in these metabolic and signaling processes (1) contribute to age-related memory loss, (2) explain the trajectory of cognitive decline in individuals and (3) could represent an effective prevention target.
1. Role of Subiculum astrocytes
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Our brain encodes, stores and retrieves our memories. Learning induces an increase in the efficiency of synaptic communication between neurons. A growing body of experimental evidence shows that the activity of these synapses is tightly controlled by the astrocytes that surround them. Yet the contribution of these glial cells to memory processes remains largely unexplored. The hippocampal formation plays an essential role in learning and memory. The latest data show that the subiculum (SUB), located between the hippocampus and the entorhinal cortex, is a key component of this hippocampal formation. Importantly, the SUB is one of the first regions affected by Alzheimer’s disease in patients and animal models. The contribution of astrocytes to memory processes in the SUB remains unexplored, both under physiological conditions and in Alzheimer’s disease. As part of an international project, we propose to characterize SUB astrocytes anatomically, molecularly and functionally, and to determine whether and how aberrations in metabolic interactions between SUB neurons and astrocytes contribute to memory deficits occurring in a mouse model of Alzheimer’s disease.
2. Role of astrocytes in cognitive aging
With increasing longevity, cognitive impairment has become among the most common age-related sources of disability and dependence and represent a huge societal burden. Twenty percent of Europeans are 65 years or over and 10 million persons suffer from dementia in EU. This number is expected to rise to 19 million by 2050, reaching 3% of the population. Preventive and therapeutic strategies capable of reducing the risk of these diseases would have a tremendous public health impact. Significant progresses have been made over the past 40 years in uncovering the biological mechanisms of learning and memory. However, neuronal signaling seems to provide only a partial explanation for those complex cognitive processes. Early brain metabolic disturbances have been reported decades before memory deficits occur but it is not yet known whether and how they contribute to the cognitive defects. Our project posits that mnesic processes are coordinated by neuronal-glial metabolic interactions and that metabolic health can influence brain plasticity and cognition.
| We think that incorporating glial biology into the cellular mechanisms of learning and memory represents a significant paradigm shift in the field that may provide new avenues for research to help solve longstanding questions both in the healthy and diseased brain. By deciphering the cerebral metabolic underpinnings of cognitive aging, the overarching ambition of the project is to shed light on novel metabolic-related pathways focusing on neuron-glia interactions. Targeting these pathways with specific interventions would greatly increase the likelihood of successful prevention. |  |
• 2018 – 2023 Agence Nationale de la Recherche (ANR), PRC
“Contributions of astrocytes to cognitive deficits induced by Tau in Alzheimer Disease”
• 2018 – 2021 France Parkinson
“Interaction fonctionnelle entre alpha-synucléine et LRRK2 et son rôle dans les dysfonctionnements mitochondriaux dans la maladie et Parkinson”
• 2020 – 2024 Fondation Alzheimer – Fondation pour la Recherche Médicale (FRM)
“Imaging glycolytic and vascular dysfunction in early Alzheimer Disease”
• 2022 – 2024 Agence Nationale de la Recherche (ANR)
“How energy metabolism shapes our memory: news insights from fly to human”
• 2023 – 2026 Agence Nationale de la Recherche (ANR), PRCI
“Metabolic Imaging of Subiculum in Alzheimer’s Disease”
• 2021 – 2026 Agence Nationale de la Recherche (ANR)
“Investigating the role of the Sideroflexin family of mitochondrial metabolites transporters in iron homeostasis and ferroptosis”
• 2016 – 2017 Fondation Plan Alzheimer
“Role of astrocytic 3-phosphoglycerate dehydrogenase in AD”
• 2013 – 2015 Association France Alzheimer / Fondation de France : Bruno Cauli (CNRS UMR 7102, UMPC), Stéphane Oliet (INSERM U862, Bordeaux)
“Towards a gene therapy targeting astrocytes in AD”
2021
• Astrocyte-neuron metabolic cooperation shapes brain activity. Bonvento G, Bolaños JP. Cell Metab. 2021 Aug 3;33(8):1546-1564. Pubmed DOI: 10.1016/j.cmet.2021.07.006
• Neuronal tau species transfer to astrocytes and induce their loss according to tau aggregation state. Maté de Gérando A, d’Orange M, Augustin E, Joséphine C, Aurégan G, Gaudin-Guérif M, Guillermier M, Hérard AS, Stimmer L, Petit F, Gipchtein P, Jan C, Escartin C, Selingue E, Carvalho K, Blum D, Brouillet E, Hantraye P, Gaillard MC, Bonvento G, Bemelmans AP, Cambon K. Brain. 2021 May 7;144(4):1167-1182. Pubmed DOI: 10.1093/brain/awab011
2020
• Impairment of Glycolysis-Derived l-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer’s Disease. Le Douce J, Maugard M, Veran J, Matos M, Jégo P, Vigneron PA, Faivre E, Toussay X, Vandenberghe M, Balbastre Y, Piquet J, Guiot E, Tran NT, Taverna M, Marinesco S, Koyanagi A, Furuya S, Gaudin-Guérif M, Goutal S, Ghettas A, Pruvost A, Bemelmans AP, Gaillard MC, Cambon K, Stimmer L, Sazdovitch V, Duyckaerts C, Knott G, Hérard AS, Delzescaux T, Hantraye P, Brouillet E, Cauli B, Oliet SHR, Panatier A, Bonvento G. Cell Metab. 2020 Mar 3;31(3):503-517.e8. Pubmed DOI: 10.1016/j.cmet.2020.02.004
2019
• Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour. Vicente-Gutierrez C, Bonora N, Bobo-Jimenez V, Jimenez-Blasco D, Lopez-Fabuel I, Fernandez E, Josephine C, Bonvento G, Enriquez JA, Almeida A, Bolaños JP. Nat Metab. 2019 Feb;1(2):201-211. Pubmed DOI: 10.1038/s42255-018-0031-6
2018
• The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin. Galvan L, Francelle L, Gaillard MC, de Longprez L, Carrillo-de Sauvage MA, Liot G, Cambon K, Stimmer L, Luccantoni S, Flament J, Valette J, de Chaldée M, Auregan G, Guillermier M, Joséphine C, Petit F, Jan C, Jarrige M, Dufour N, Bonvento G, Humbert S, Saudou F, Hantraye P, Merienne K, Bemelmans AP, Perrier AL, Déglon N, Brouillet E.
Brain. 2018 141:1434-1454. Pubmed DOI: 10.1093/brain/awy057
2017
• Current technical approaches to brain energy metabolism. Barros LF, Bolaños JP, Bonvento G, Bouzier-Sore AK, Brown A, Hirrlinger J, Kasparov S, Kirchhoff F, Murphy AN, Pellerin L, Robinson MB, Weber B.
Glia. 2017 Nov 7. Pubmed DOI: 10.1002/glia.23248
• Imaging and spectroscopic approaches to probe brain energy metabolism dysregulation in neurodegenerative diseases. Bonvento G, Valette J, Flament J, Mochel F, Brouillet E.
J Cereb Blood Flow Metab. 2017 Jun;37(6):1927-1943. Pubmed DOI: 10.1177/0271678X17697989
2016
• Complex I assembly into supercomplexes determines differential mitochondrial ROS production in neurons and astrocytes. Lopez-Fabuel I, Le Douce J, Logan A, James AM, Bonvento G, Murphy MP, Almeida A, Bolaños JP.
Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13063-13068 Pubmed DOI: 10.1073/pnas.1613701113
• Synaptic scaling up in medium spiny neurons of aged BACHD mice: A slow-progression model of Huntington’s disease. Rocher AB, Gubellini P, Merienne N, Boussicault L, Petit F, Gipchtein P, Jan C, Hantraye P, Brouillet E, Bonvento G.
Neurobiol Dis. 2016 Feb;86:131-139 Pubmed DOI: 10.1016/j.nbd.2015.10.016
2011
• Plasticity of astroglial networks in olfactory glomeruli. Roux L, Benchenane K, Rothstein JD, Bonvento G, Giaume C. (2011)
Proc Natl Acad Sci USA 108(45):18442-18446. Pubmed DOI: 10.1073/pnas.1107386108
2010
• In vivo expression of polyglutamine-expanded huntingtin by mouse striatal astrocytes impairs glutamate transport: a correlation with Huntington’s Disease subjects. Faideau M, Kim J, Cormier K, Gilmore R, Welch M, Auregan G, Dufour N, Guillermier M, Escartin C, Brouillet E, Hantraye P, Déglon N, Ferrante RJ and Bonvento G (2010)
Hum Mol Genetics, 19:3053-3067 Pubmed
DOI: 10.1093/hmg/ddq212
Foreign students
• Ana AMARAL, Clinigene-EU Network, PhD, 2010
• Robin GUTIÉRREZ, ECOS Chili, 2011
• Rodrigo LERCHUNDI, ECOS Chili, 2012
• Tamara SOTELO, ECOS Chili, 2013
• Cristina DONATO, rotation ENP, 2015
Master 2 students
• Karine LE MOINE, DEA de Physiologie et Physiopathologie de la Nutrition Humaine, Paris 7, 1998
• Angélique REGNIER, DEA de Métabolisme énergétique et régulations nutritionnelles, Paris 7, 2001
• Touria NEHIRI, DEA de Métabolisme énergétique et régulations nutritionnelles, Paris 7, 2003
• Nicolas MERIENNE, Master 2 Strasbourg, 2012
• Marianne MAUGARD, Master 2 BIP-UPMC, 2015
• Pierre-Antoine VIGNERON, Master 2 BIP-UPMC, 2017
Phd Students
• Kamel KACEM, thèse de Neurosciences, Paris 6, soutenance 1997
• Nathalie CHOLET, thèse de Physiologie et Physiopathologie de la Nutrition Humaine, Paris 7, soutenance 1999
• Carole ESCARTIN, thèse de Neurosciences, Paris 6, soutenance 20/01/2006
• Angélique COLIN, thèse de Neurosciences, Paris 6, soutenance 17/12/2008
• Mathilde FAIDEAU, thèse de Neurosciences, Paris 6, soutenance 9/12/2009
• Lydie BOUSSICAULT, thèse de Neurosciences, Paris 6, soutenance 21/06/2013
• Juliette LE DOUCE, thèse de Neurosciences, Paris 6, soutenance 14/12/2015
• Marianne MAUGARD, thèse de Neurosciences, Paris-Sud, financement ENS, soutenance 09/2018
• Pierre-Antoine VIGNERON, thèse de Neurosciences, Paris-Saclay, financement FRM, soutenance 10/2020
• Emma AUGUSTIN, thèse de Neurosciences, Paris-Saclay, financement ANR, soutenance 12/2023
Postdocs
• Brigitte VOUTSINOS-PORCHE, Human Frontier Science Program, février 1999-décembre 2001
• Aïcha DOUHOU, contrat CFR-CEA, octobre 2003 – octobre 2005
• Anne-Sophie HERARD, Contrat Imagerie du Petit Animal, décembre 2003-juin 2005
• Claire MARTIN, ANR AstroGLO, octobre 2008 – octobre 2009
• Anne ROCHER, FP7-Marie-Curie, juillet 2010-juillet 2012
• Emilie FAIVRE, ANR MetALZ, avril 2012-novembre 2013
• Pierrick JEGO, Eurotalents CEA, EU, en cours, fin septembre 2017
• Emmanuel THAN-TRONG, Fondation ALZ, septembre 2020-décembre 2023
