Endogenous Activation of mGlu5 Metabotropic Glutamate Receptors Is Required for Oligodendrocyte Maturation and Myelinogenesis in Mice

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mGlu5 metabotropic glutamate receptors are highly expressed and functional in early postnatal life, but their role in brain development remains to be elucidated. We now report that mGlu5−/− mice showed a large reduction in mRNA and protein levels of myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), and myelin basic protein (MBP) in the cerebral cortex and cerebellum at postnatal day (PND) 14. Expression of these proteins reflects oligodendrocyte differentiation and myelin formation in the CNS, a process that is prominent in the second week of postnatal life in mice. Expression of myelin markers recovered at later developmental stages, with the exception of MAG and MBP levels in the cerebellum, which were still reduced in mGlu5−/− mice. We also observed a large reduction in myelin protein markers in the cerebral cortex and cerebellum of mice treated with the mGlu5 receptor negative allosteric modulator MTEP (3 mg/kg, i.p.) from PND 7 to PND 14. MTEP-treated mice also showed reduced motor coordination and sensorimotor function at PND 14. Treatment with MTEP reduced oligodendrocyte maturation without affecting proliferation of oligodendrocyte progenitor cells in primary cultures prepared from the rat cerebral cortex. These findings suggest that endogenous activation of mGlu5 receptors contributes to myelin formation during postnatal development in mice.

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