Abstract
Experience and changes in neuronal activity can alter CNS myelination, but the signalling pathways responsible remain poorly understood. Here we define a pathway in which endothelin, signalling through the G protein-coupled receptor endothelin receptor B and PKC epsilon, regulates the number of myelin sheaths formed by individual oligodendrocytes in mouse and zebrafish. We show that this phenotype is also observed in the prefrontal cortex of mice following social isolation, and is associated with reduced expression of vascular endothelin. Additionally, we show that increasing endothelin signalling rescues this myelination defect caused by social isolation. Together, these results indicate that the vasculature responds to changes in neuronal activity associated with experience by regulating endothelin levels, which in turn affect the myelinating capacity of oligodendrocytes. This pathway may be employed to couple the metabolic support function of myelin to activity-dependent demand and also represents a novel mechanism for adaptive myelination.
Highlights
There is increasing evidence that experience regulates CNS myelination
Prior work has established that social isolation in mice during a critical period comprising 2 weeks after weaning reduces both the excitability of specific subtypes of pyramidal neurons of the medial prefrontal cortex and oligodendrocyte formation and myelination in the same area (Liu et al, 2012, Makinodan et al, 2012, Yamamuro et al, 2018) We repeated this protocol, confirming the previously-described effect on circuit function by showing that isolated mice spent significantly less time than socially-experienced controls interacting with a novel mouse
Using this approach we showed that individual oligodendrocytes made fewer myelin sheaths, the length of the myelin sheaths formed by oligodendrocytes in these mice was unaffected
Summary
There is increasing evidence that experience regulates CNS myelination. For example, social interactions, sensory stimulation and several forms of learning have been shown to alter white matter and myelin structure in both humans and animal models (Scholz et al, 2009, Makinodan et al, 2012, Liu et al, 2012, Sampaio-Baptista et al, 2013, McKenzie et al, 2014, Etxeberria et al., 2016, Xiao et al, 2016, Hughes et al, 2018). At the level of individual neurons and axons, increasing the level of activity by using optogenetics or chemogenetics enhances the generation of myelinforming oligodendrocytes and increases the amount of myelin they form (Gibson et al, 2014, Mitew et al, 2018), whilst preventing synaptic vesicular release from axons reduces myelin formation (Hines et al, 2015, Mensch et al, 2015, Koudelka et al, 2016). Together, these findings have led to a new concept of CNS plasticity - adaptive myelination. Such changes could in turn contribute to the alterations in conduction that underpin CNS neural circuit plasticity (Sampaio-Baptista and Johansen-Berg, 2017, Foster et al, 2019, Suminaite et al., 2019)
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