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PEOPLE
KEYWORDS
Oligodendrocytes
GABA receptors
Glutamate receptors
White matter injury
TECHNIQUES
EAE (MS model)
Cell Culture
Immunofluorescence
Electron microscopy
GABAB receptors in oligodendrocytes for (re)myelination
Myelin formation in the central nervous system is driven by oligodendrocytes, which must differentiate from oligodendrocyte progenitor cells (OPCs) in order to perform their role. Gamma-aminobutiric acid (GABA) is an inhibitory neurotransmitter of the central nervous system that has been described as a relevant modulator of OPC differentiation and functions, as part of the regulation driven by neuron-OL communication. Adverse myelination or oligodendrocyte functionality has been linked to several pathologies such as Alzheimer’s Disease, schizophrenia or autism spectrum disorders (ASD), and remarkably, OPC differentiation impairment and myelin damage is critical in demyelinating diseases such as multiple sclerosis (MS).
Given the potential to modulate oligodendrocyte plasticity through GABAergic signaling and particularly through GABAB receptors, our main research goals are:
Identifying the molecular mechanisms associated to GABAB receptor activation in the oligodendroglial lineage.
Evaluating the impact of GABAB receptor modulation in models of demyelination.
With that aim, we make use of molecular and histological techniques, combining in vitro primary cultures, animal models of demyelinating diseases, transgenic mice and patient samples.
Funded by Ministerio de Ciencia e Innovación
Primary oligodendrocytes (cyan) in culture. Nuclei in magenta.
Role of oligodendrocyte NMDA receptors in autoimmune encephalitis
Antibodies against neuronal N-methyl-D-aspartate receptors (NMDARs) in patients with anti-NMDAR encephalitis alter neuronal synaptic function and plasticity, but the effects on other cells of the nervous system are unknown. By using cerebrospinal fluid from patients, full of anti-NMDARs antibodies, we have determined alterations in oligodendrocyte function. Antibodies from patients with anti-NMDAR encephalitis specifically alter the function of NMDARs in oligodendrocytes, causing a decrease of expression of GLUT1 and NMDA-dependent cytosolic calcium response. Considering that normal GLUT1 expression in oligodendrocytes and myelin is needed to metabolically support axonal function, the findings suggest a link between antibody-mediated dysfunction of NMDARs in oligodendrocytes and the white matter alterations reported in patients with this disorder.
Funded by CIBERNED, Basque Government and Ministerio de Ciencia e Innovación
Patients' NMDA auto-antibodies reduce the expression of glucose-transporter 1, needed for proper metabolic function
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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