Myelin, the lipid bilayer wrapping axons, contributes to increasing the conduction velocity of axons and to providing axonal metabolic support. Oligodendrocytes myelinate central nervous system axons in a precisely orchestrated and regulated process, which takes place predominantly postnatally. The oligodendrocyte lineage and myelination have recently been identified as contributing to autism spectrum disorder (ASD). The aberrant development of white matter found in patients with ASD and the deficits observed in myelin in ASD mice models are suggestive of disruptions in the maturation of oligodendrocytes. However, the therapeutic potential of interventions intended to increase oligodendrocyte differentiation and/or myelination has not been tested in ASD animal models. Importantly, myelination is a much more plastic process than previously thought; it can be manipulated by pharmacologically targeting the proliferation and differentiation of oligodendrocyte progenitor cells or by directly promoting myelinogenesis.

To address this question, María Domercq and her colleagues at the Achucarro Basque Center for Neuroscience will seek to determine whether boosting myelination restores myelin deficits and reverses behavioral symptoms in an ASD mice model, Cntnap2-/- mice. First, they will test the impact of drugs capable of increasing the differentiation of oligodendrocyte progenitor cells into myelinating oligodendrocytes. Second, they will directly promote myelination using chemogenetics. For this purpose, they have developed transgenic mice in which selective activation of oligodendrocytes increases myelination and augments the conduction velocity of the axons in white and gray matter. This transgenic mouse line will enable them to modify myelination selectively and analyze its impact on cognitive and social behavior in Cntnap2-/- mice.

Data obtained from this project may reveal new mechanisms involved in ASD pathogenesis and provide support for novel intervention strategies based on increasing the plasticity of myelination.