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Cold Spring Harbor Perspectives in... Jun 2015Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin... (Review)
Review
Myelinated nerve fibers have evolved to enable fast and efficient transduction of electrical signals in the nervous system. To act as an electric insulator, the myelin sheath is formed as a multilamellar membrane structure by the spiral wrapping and subsequent compaction of the oligodendroglial plasma membrane around central nervous system (CNS) axons. Current evidence indicates that the myelin sheath is more than an inert insulating membrane structure. Oligodendrocytes are metabolically active and functionally connected to the subjacent axon via cytoplasmic-rich myelinic channels for movement of macromolecules to and from the internodal periaxonal space under the myelin sheath. This review summarizes our current understanding of how myelin is generated and also the role of oligodendrocytes in supporting the long-term integrity of myelinated axons.
Topics: Axons; Glycolysis; Models, Biological; Myelin Sheath; Oligodendroglia; Synaptic Transmission
PubMed: 26101081
DOI: 10.1101/cshperspect.a020479 -
Cold Spring Harbor Perspectives in... Jun 2015Myelinated nerve fibers are essential for the rapid propagation of action potentials by saltatory conduction. They form as the result of reciprocal interactions between... (Review)
Review
Myelinated nerve fibers are essential for the rapid propagation of action potentials by saltatory conduction. They form as the result of reciprocal interactions between axons and Schwann cells. Extrinsic signals from the axon, and the extracellular matrix, drive Schwann cells to adopt a myelinating fate, whereas myelination reorganizes the axon for its role in conduction and is essential for its integrity. Here, we review our current understanding of the development, molecular organization, and function of myelinating Schwann cells. Recent findings into the extrinsic signals that drive Schwann cell myelination, their cognate receptors, and the downstream intracellular signaling pathways they activate will be described. Together, these studies provide important new insights into how these pathways converge to activate the transcriptional cascade of myelination and remodel the actin cytoskeleton that is critical for morphogenesis of the myelin sheath.
Topics: Action Potentials; Epigenesis, Genetic; Humans; Myelin Sheath; Nerve Fibers, Myelinated; Schwann Cells; Signal Transduction; Transcription, Genetic
PubMed: 26054742
DOI: 10.1101/cshperspect.a020529 -
Physiological Reviews Jul 2019Oligodendrocytes generate multiple layers of myelin membrane around axons of the central nervous system to enable fast and efficient nerve conduction. Until recently,... (Review)
Review
Oligodendrocytes generate multiple layers of myelin membrane around axons of the central nervous system to enable fast and efficient nerve conduction. Until recently, saltatory nerve conduction was considered the only purpose of myelin, but it is now clear that myelin has more functions. In fact, myelinating oligodendrocytes are embedded in a vast network of interconnected glial and neuronal cells, and increasing evidence supports an active role of oligodendrocytes within this assembly, for example, by providing metabolic support to neurons, by regulating ion and water homeostasis, and by adapting to activity-dependent neuronal signals. The molecular complexity governing these interactions requires an in-depth molecular understanding of how oligodendrocytes and axons interact and how they generate, maintain, and remodel their myelin sheaths. This review deals with the biology of myelin, the expanded relationship of myelin with its underlying axons and the neighboring cells, and its disturbances in various diseases such as multiple sclerosis, acute disseminated encephalomyelitis, and neuromyelitis optica spectrum disorders. Furthermore, we will highlight how specific interactions between astrocytes, oligodendrocytes, and microglia contribute to demyelination in hereditary white matter pathologies.
Topics: Aging; Animals; Central Nervous System; Demyelinating Diseases; Humans; Myelin Sheath
PubMed: 31066630
DOI: 10.1152/physrev.00031.2018 -
Cold Spring Harbor Perspectives in... Aug 2015Oligodendrocyte precursor cells (OPCs) originate in the ventricular zones (VZs) of the brain and spinal cord and migrate throughout the developing central nervous system... (Review)
Review
Oligodendrocyte precursor cells (OPCs) originate in the ventricular zones (VZs) of the brain and spinal cord and migrate throughout the developing central nervous system (CNS) before differentiating into myelinating oligodendrocytes (OLs). It is not known whether OPCs or OLs from different parts of the VZ are functionally distinct. OPCs persist in the postnatal CNS, where they continue to divide and generate myelinating OLs at a decreasing rate throughout adult life in rodents. Adult OPCs respond to injury or disease by accelerating their cell cycle and increasing production of OLs to replace lost myelin. They also form synapses with unmyelinated axons and respond to electrical activity in those axons by generating more OLs and myelin locally. This experience-dependent "adaptive" myelination is important in some forms of plasticity and learning, for example, motor learning. We review the control of OL lineage development, including OL population dynamics and adaptive myelination in the adult CNS.
Topics: Animals; Brain; Homeostasis; Intercellular Signaling Peptides and Proteins; Mammals; Myelin Sheath; Oligodendroglia; Spinal Cord; Synaptic Transmission
PubMed: 26492571
DOI: 10.1101/cshperspect.a020453 -
Neurotherapeutics : the Journal of the... Oct 2021Myelin is a key evolutionary specialization and adaptation of vertebrates formed by the plasma membrane of glial cells, which insulate axons in the nervous system.... (Review)
Review
Myelin is a key evolutionary specialization and adaptation of vertebrates formed by the plasma membrane of glial cells, which insulate axons in the nervous system. Myelination not only allows rapid and efficient transmission of electric impulses in the axon by decreasing capacitance and increasing resistance but also influences axonal metabolism and the plasticity of neural circuits. In this review, we will focus on Schwann cells, the glial cells which form myelin in the peripheral nervous system. Here, we will describe the main extrinsic and intrinsic signals inducing Schwann cell differentiation and myelination and how myelin biogenesis is achieved. Finally, we will also discuss how the study of human disorders in which molecules and pathways relevant for myelination are altered has enormously contributed to the current knowledge on myelin biology.
Topics: Animals; Axons; Biology; Humans; Myelin Sheath; Neuroglia; Schwann Cells
PubMed: 34244924
DOI: 10.1007/s13311-021-01083-w -
Neuron Aug 2018To address the significance of enhancing myelination for functional recovery after white matter injury (WMI) in preterm infants, we characterized hypomyelination...
To address the significance of enhancing myelination for functional recovery after white matter injury (WMI) in preterm infants, we characterized hypomyelination associated with chronic hypoxia and identified structural and functional deficits of excitatory cortical synapses with a prolonged motor deficit. We demonstrate that genetically delaying myelination phenocopies the synaptic and functional deficits observed in mice after hypoxia, suggesting that myelination may possibly facilitate excitatory presynaptic innervation. As a gain-of-function experiment, we specifically ablated the muscarinic receptor 1 (M1R), a negative regulator of oligodendrocyte differentiation in oligodendrocyte precursor cells. Genetically enhancing oligodendrocyte differentiation and myelination rescued the synaptic loss after chronic hypoxia and promoted functional recovery. As a proof of concept, drug-based myelination therapies also resulted in accelerated differentiation and myelination with functional recovery after chronic hypoxia. Together, our data indicate that myelination-enhancing strategies in preterm infants may represent a promising therapeutic approach for structural/functional recovery after hypoxic WMI.
Topics: Animals; Animals, Newborn; Chronic Disease; Female; Hypoxia; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myelin Sheath; Neurogenesis; Oligodendroglia; Receptor, Muscarinic M1; Recovery of Function; Synapses
PubMed: 30078577
DOI: 10.1016/j.neuron.2018.07.017 -
Neuron Jul 2021Severe cognitive decline is a hallmark of Alzheimer's disease (AD). In addition to gray matter loss, significant white matter pathology has been identified in AD...
Severe cognitive decline is a hallmark of Alzheimer's disease (AD). In addition to gray matter loss, significant white matter pathology has been identified in AD patients. Here, we characterized the dynamics of myelin generation and loss in the APP/PS1 mouse model of AD. Unexpectedly, we observed a dramatic increase in the rate of new myelin formation in APP/PS1 mice, reminiscent of the robust oligodendroglial response to demyelination. Despite this increase, overall levels of myelination are decreased in the cortex and hippocampus of APP/PS1 mice and postmortem AD tissue. Genetically or pharmacologically enhancing myelin renewal, by oligodendroglial deletion of the muscarinic M1 receptor or systemic administration of the pro-myelinating drug clemastine, improved the performance of APP/PS1 mice in memory-related tasks and increased hippocampal sharp wave ripples. Taken together, these results demonstrate the potential of enhancing myelination as a therapeutic strategy to alleviate AD-related cognitive impairment.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cerebral Cortex; Cognitive Dysfunction; Disease Models, Animal; Maze Learning; Mice; Mice, Transgenic; Myelin Sheath; Presenilin-1
PubMed: 34102111
DOI: 10.1016/j.neuron.2021.05.012 -
Glia Apr 2018Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is... (Review)
Review
Myelinating cells surround axons to accelerate the propagation of action potentials, to support axonal health, and to refine neural circuits. Myelination is metabolically demanding and, consistent with this notion, mTORC1-a signaling hub coordinating cell metabolism-has been implicated as a key signal for myelination. Here, we will discuss metabolic aspects of myelination, illustrate the main metabolic processes regulated by mTORC1, and review advances on the role of mTORC1 in myelination of the central nervous system and the peripheral nervous system. Recent progress has revealed a complex role of mTORC1 in myelinating cells that includes, besides positive regulation of myelin growth, additional critical functions in the stages preceding active myelination. Based on the available evidence, we will also highlight potential nonoverlapping roles between mTORC1 and its known main upstream pathways PI3K-Akt, Mek-Erk1/2, and AMPK in myelinating cells. Finally, we will discuss signals that are already known or hypothesized to be responsible for the regulation of mTORC1 activity in myelinating cells.
Topics: Animals; Humans; Myelin Sheath; TOR Serine-Threonine Kinases
PubMed: 29210103
DOI: 10.1002/glia.23273 -
Neuron Dec 2020Myelination facilitates rapid axonal conduction, enabling efficient communication across different parts of the nervous system. Here we examined mechanisms controlling...
Myelination facilitates rapid axonal conduction, enabling efficient communication across different parts of the nervous system. Here we examined mechanisms controlling myelination after injury and during axon regeneration in the central nervous system (CNS). Previously, we discovered multiple molecular pathways and strategies that could promote robust axon regrowth after optic nerve injury. However, regenerated axons remain unmyelinated, and the underlying mechanisms are elusive. In this study, we found that, in injured optic nerves, oligodendrocyte precursor cells (OPCs) undergo transient proliferation but fail to differentiate into mature myelination-competent oligodendrocytes, reminiscent of what is observed in human progressive multiple sclerosis. Mechanistically, we showed that OPC-intrinsic GPR17 signaling and sustained activation of microglia inhibit different stages of OPC differentiation. Importantly, co-manipulation of GPR17 and microglia led to extensive myelination of regenerated axons. The regulatory mechanisms of stage-dependent OPC differentiation uncovered here suggest a translatable strategy for efficient de novo myelination after CNS injury.
Topics: Animals; Axons; Cell Differentiation; Cell Proliferation; Female; Male; Mice; Mice, Transgenic; Microglia; Myelin Sheath; Nerve Fibers, Myelinated; Nerve Regeneration; Nerve Tissue Proteins; Oligodendrocyte Precursor Cells; Random Allocation; Receptors, G-Protein-Coupled
PubMed: 33108748
DOI: 10.1016/j.neuron.2020.09.016 -
Cells Mar 2020Myelin is critical for the proper function of the nervous system and one of the most complex cell-cell interactions of the body. Myelination allows for the rapid... (Review)
Review
Myelin is critical for the proper function of the nervous system and one of the most complex cell-cell interactions of the body. Myelination allows for the rapid conduction of action potentials along axonal fibers and provides physical and trophic support to neurons. Myelin contains a high content of lipids, and the formation of the myelin sheath requires high levels of fatty acid and lipid synthesis, together with uptake of extracellular fatty acids. Recent studies have further advanced our understanding of the metabolism and functions of myelin fatty acids and lipids. In this review, we present an overview of the basic biology of myelin lipids and recent insights on the regulation of fatty acid metabolism and functions in myelinating cells. In addition, this review may serve to provide a foundation for future research characterizing the role of fatty acids and lipids in myelin biology and metabolic disorders affecting the central and peripheral nervous system.
Topics: Animals; Fatty Acids; Humans; Lipid Metabolism; Models, Biological; Myelin Sheath; Oxidation-Reduction
PubMed: 32230947
DOI: 10.3390/cells9040812