Signaling pathwais in oligodentdrocytes to promote myelin remodeling

Abstract

Oligodendrocytes make myelin and support axons metabolically with lactate. Experience and neuronal activity can induce dynamic changes in myelination during development and in adult life, suggesting a new form of plasticity to adapt brain function to environmental stimuli. Myelin remodelling is driven mainly by newly-formed oligodendrocytes from precursors cells. However, the role of mature oligodendrocytes in plastic changes of myelin is practically unknown. We have generated transgenic mice, using the CreERT2-lox technology, overexpressing the DREADD receptor hM3Dq under the PLP promoter, specific of mature oligodendrocytes. Chronic stimulation of hM3Dq receptors induced an increase in myelination of axons in cerebral cortex and corpus callosum, and consequently, an increase in axonal conduction velocity of interhemispheric callosal connections. Importantly, acute stimulation of hM3Dq+ activates metabolism in oligodendrocytes that maintained axonal function under high frequency stimulation and prevented axonal damage secondary to oxygen glucose deprivation. Mature oligodendrocytes stimulation promoted remyelination and protected axons in demyelinating disease models. Our data show that pharmacogenetic oligodendrocyte stimulation ameliorates motor symptoms of mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Taken together, these findings indicate that this pharmacogenetic mouse line is a very useful tool to elucidate the contribution of mature oligodendrocytes to myelin remodeling in physiological and pathological conditions, and reveals a novel role of myelin-axon lactate shuttle in axonal protection.