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PEOPLE
KEYWORDS
Myelin
Metabolic disorders
Neurodegenerative diseases
TECHNIQUES
Genetic manipulation
Cell Culture
Immunofluorescence
Electron microscopy
Myelin as a source of energy
Myelin is a multilamellar sheath enriched in lipids and sustained by proteins. It insulates axons to allow electrical impulses to transmit quickly and efficiently along the nerve cells. Defects in myelination drive to diseases such as multiple sclerosis. Central Nervous System myelin is produced by oligodendrocytes, brain cells that express several G protein-coupled receptors (GPCRs) involved in myelination. However, the impact of oligodendrocyte activation in myelin content remains unknown. The goal of MYELINPLUS is to unravel the effect of oligodendrocyte activation in myelin condition and consumption through energy metabolism in vivo. To that end, we will use Designer Receptors Exclusively Activated by Designer Drugs, DREADDS, GPCRs that have been engineered to only respond to synthetic ligands. We propose to generate a conditional mouse strain that will express a Gs-DREADD only in oligodendrocytes. This strategy will allow the specific activation of oligodendrocytes in living animals, to study the effects on myelin dynamics: myelin quantity, structure, neuronal transmission and cognition. In addition, we will evaluate the effects of oligodendrocyte stimulation in myelin as a source of energy in the brain in strenuous exercise and in metabolic disorders. This knowledge will pave the way for the development of new strategies targeting GPCR in oligodendrocytes that can ameliorate demyelinating and neurodegenerative diseases.
Publications related to this topic
Serrano-Regal MP, Bayón-Cordero L, Chara Ventura JC, Ochoa-Bueno BI, Tepavcevic V, Matute C, Sánchez-Gómez MV. GABAB receptor agonist baclofen promotes central nervous system remyelination. Glia. 2022 Aug 18. [LINK]
Bayón-Cordero L, Ochoa-Bueno BI, Ruiz A, Ozalla M, Matute C, Sánchez-Gómez MV. GABA Receptor Agonists Protect From Excitotoxic Damage Induced by AMPA in Oligodendrocytes. Front Pharmacol. 2022 Jul 26;13:897056. [LINK]
Serrano-Regal MP, Luengas-Escuza I, Bayón-Cordero L, Ibarra-Aizpurua N, Alberdi E, Pérez-Samartín A, Matute C, Sánchez-Gómez MV. Oligodendrocyte Differentiation and Myelination Is Potentiated via GABAB Receptor Activation. Neuroscience 2020; 439: 163–180. [LINK]
Matute C, Palma A, Serrano-Regal MP, Maudes E, Barman S, Sánchez-Gómez MV, Domercq M, Goebels N, Dalmau J. N-Methyl-D-Aspartate Receptor Antibodies in Autoimmune Encephalopathy Alter Oligodendrocyte Function. Ann Neurol 2020; 87: 670–676. [LINK]
Serrano-Regal MP, Bayón-Cordero L, Ordaz RP, Garay E, Limon A, Arellano RO, Matute C, Sánchez-Gómez MV. Expression and Function of GABA Receptors in Myelinating Cells. Front Cell Neurosci 2020; 14: 256. [LINK]
Arellano RO, Sánchez-Gómez MV, Alberdi E, Canedo-Antelo M, Chara JC, Palomino A, Pérez-Samartín A, Matute C. Axon-to-Glia Interaction Regulates GABAA Receptor Expression in Oligodendrocytes. Mol Pharmacol 2016; 89: 63–74. [LINK]
Domercq M, Perez-Samartin A, Aparicio D, Alberdi E, Pampliega O, Matute C. P2X7 receptors mediate ischemic damage to oligodendrocytes. Glia 2010; 58: 730–740. [LINK]
Matute C, Torre I, Pérez-Cerdá F, Pérez-Samartín A, Alberdi E, Etxebarria E, Arranz AM, Ravid R, Rodríguez-Antigüedad A, Sánchez-Gómez M, Domercq M. P2X(7) receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates experimental autoimmune encephalomyelitis. J Neurosci 2007; 27: 9525–9533. [LINK]
Sánchez-Gómez MV, Alberdi E, Ibarretxe G, Torre I, Matute C. Caspase-dependent and caspase-independent oligodendrocyte death mediated by AMPA and kainate receptors. J Neurosci 2003; 23: 9519–9528. [LINK]
Matute C, Sánchez-Gómez MV, Martínez-Millán L, Miledi R. Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes. PNAS 1997; 94: 8830–8835. [LINK]
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