Oligodendrocytes, the myelinating glial cells of the central nervous system (CNS), surround axons with their membrane extensions, forming the myelin sheath. Loss of oligodendrocytes and/or myelin (demyelination) occurs in traumatic brain injury or pathologies such as multiple sclerosis. Since, there is no specific treatment for demyelination; we are interested in enhancing myelin endogenous repair. We focus our work on A Disintegrin and Metalloprotease (ADAM) 10, the major CNS α-secretase, which generates the neuroprotective soluble fragment sAPPα via cleavage of the Amyloid Precursor Protein (APP). Previous results from the team have shown that the pharmacological activation of ADAM10 has a protective effect against demyelination and enhanced remyelination ex vivo and in vivo. To investigate the role of oligodendroglial ADAM10 in the de/re/myelination processes, we have generated a novel mouse strain, KOOLA10, in which we invalidated ADAM10 in oligodendrocyte at different important time points during oligodendrogenesis or myelination. Our findings showed that the maturation of primary cultures of ADAM10-deficient is delayed and that myelin sheaths are thinner in the cerebellum of adult KOOLA10 mice, with shorter distance between layers. Moreover, we observed a long-term impairment of cognitive and motor behavior in mice. Taken together our results suggest that ADAM10 may be an architect of myelin dynamics, playing a role from OPC maturation through to behavior.