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  • br Activity dependent control of myelination and myelin

    2022-08-04


    Activity-dependent control of myelination and myelin maintenance Oligodendrocytes have intrinsic myelinating capacity and can myelinate fixed TTP 22 in addition to synthetic nanofibers and micropillars [21, 34, 35]. What prevents oligodendrocytes from myelinating dendrites or other cells in the CNS? Using a candidate approach, Redmond et al. identified the transmembrane protein JAM2 as a negative regulator of oligodendrocyte myelination (Figure 2). Overexpression of extracellular Fc-tagged JAM2 attenuated the ability of oligodendrocytes to myelinate micropillars, and loss of Jam2 in a mouse model caused an increase in myelinated neuronal cell bodies, implicating repulsive cues in modulating myelination []. Another study indicates that a component of intrinsic myelination may be hardwired in oligodendrocytes. When plated on microfibers, spinal cord OPCs differentiated and produced longer myelin sheaths than cortex-derived OPCs []. Are these regional differences due to environmental cues or other factors? One possibility is that there are specific subtypes of oligodendrocytes with distinct myelinating capacities. To this end, single-cell RNA sequencing was used to characterize cell types in the murine hippocampus and cortex. Interestingly, findings from these experiments suggested seven distinct subtypes of oligodendrocytes, including OPCs [38]. Furthermore, a recent study using the same technique to probe oligodendrocyte heterogeneity in more detail proposed 13 distinct populations of oligodendrocytes in the mouse brain []. While negative regulators prevent aberrant myelination in the CNS, variation in myelin distribution along single axons of the developing cortex suggests a fine-tuning of myelination capacity beyond an intrinsic program [40]. Indeed, early work implicated electrical signaling as an instructive cue in oligodendrocyte development and myelination [41, 42]. How might activity influence myelination? Previous work demonstrated that neurons form functional synapses on OPCs [43]. Recent research suggests, however, that while oligodendrocytes are more likely to myelinate electrically active axons, this occurs independently of synapse formation, instead relying on vesicular release of glutamate and ATP [44]. A critical role for vesicle transport in myelination was confirmed in vivo using zebrafish. Mensch and colleagues used tetanus toxin to inhibit vesicular release, resulting in fewer sheaths, while increasing activity led to more sheaths per oligodendrocyte []. In a complementary study, Hines et al. found that initial oligodendrocyte axon ensheathment is activity independent, but preferential contact is maintained on axons releasing vesicles. Processes are either retracted from inactive axons or produce shorter myelin sheaths (Figure 2) []. However, the necessity of vesicular release is differentially regulated in the CNS. This cue is important for proper myelination by reticulospinal neurons but not by commissural primary ascending (CoPA) neurons []. Why there are different regulatory mechanisms depending on neuronal subtype is an area of future investigation. Rather than a simple static insulator deposited during development, myelin is now recognized as a player in nervous system plasticity. Myelination during development and in adulthood is modulated by an animal's social experience [48, 49] and myelin remodeling occurs throughout life [50]. Furthermore, learning new skills, such as juggling and language acquisition, results in changes to myelin [51, 52]. How do myelin alterations occur and how do they affect nervous system plasticity? One possibility is that activity stimulates formation of new oligodendrocytes. To this end, it was shown that differentiation of oligodendrocytes from precursors is necessary for mice to learn a new skill effectively [53], and that neuronal activity promotes oligodendrogenesis and concomitant behavior changes [54]. What is the role of new oligodendrocytes? A recent paper examined the timing of oligodendrogenesis in response to learning and found significant formation of new oligodendrocytes in mice learning to navigate a complex wheel within the first 2.5hours. Furthermore, mice unable to form new oligodendrocytes exhibit learning deficits as early as 2-3hours after first encountering the wheel. This early necessity for new oligodendrocytes in the learning process indicates a level of active involvement []. Whether this occurs through modifying circuits, providing metabolic support or an as yet undetermined mechanism is an area of future investigation.