The bright and the dark side of myelin plasticity: Neuron-glial interactions in health and disease.

Neuron-glial interactions shape neural circuit establishment, refinement and function. One of the key neuron-glial interactions takes place between axons and oligodendroglial precursor cells. Interactions between neurons and oligodendrocyte precursor cells (OPCs) promote OPC proliferation, generation of new oligodendrocytes and myelination, shaping myelin development and ongoing adaptive myelin plasticity in the brain. Communication between neurons and OPCs can be broadly divided into paracrine and synaptic mechanisms. Following the Nobel mini-symposium "The Dark Side of the Brain" in late 2019 at the Karolinska Institutet, this mini-review will focus on the bright and dark sides of neuron-glial interactions and discuss paracrine and synaptic interactions between neurons and OPCs and their malignant counterparts

White Matter Plasticity Keeps the Brain in Tune: Axons Conduct While Glia Wrap.

Precise timing of neuronal inputs is crucial for brain circuit function and development, where it contributes critically to experience-dependent plasticity. Myelination therefore provides an important adaptation mechanism for vertebrate circuits. Despite its importance to circuit activity, the interplay between neuronal activity and myelination has yet to be fully elucidated. In recent years, significant attention has been devoted to uncovering and explaining the phenomenon of white matter (WM) plasticity. Here, we summarize some of the critical evidence for modulation of the WM by neuronal activity, ranging from human diffusion tensor imaging (DTI) studies to experiments in animal models. These experiments reveal activity-dependent changes in the differentiation and proliferation of the oligodendrocyte lineage, and in the critical properties of the myelin sheaths. We discuss the implications of such changes for synaptic function and plasticity, and present the underlying mechanisms of neuron-glia communication, with a focus on glutamatergic signaling and the axomyelinic synapse. Finally, we examine evidence that myelin plasticity may be subject to critical periods. Taken together, the present review aims to provide insights into myelination in the context of brain circuit formation and function, emphasizing the bidirectional interplay between neurons and myelinating glial cells to better inform future investigations of nervous system plasticity

White Matter Plasticity Keeps the Brain in Tune: Axons Conduct While Glia Wrap

Precise timing of neuronal inputs is crucial for brain circuit function and development, where it contributes critically to experience-dependent plasticity. Myelination therefore provides an important adaptation mechanism for vertebrate circuits. Despite its importance to circuit activity, the interplay between neuronal activity and myelination has yet to be fully elucidated. In recent years, significant attention has been devoted to uncovering and explaining the phenomenon of white matter (WM) plasticity. Here, we summarize some of the critical evidence for modulation of the WM by neuronal activity, ranging from human diffusion tensor imaging (DTI) studies to experiments in animal models. These experiments reveal activity-dependent changes in the differentiation and proliferation of the oligodendrocyte lineage, and in the critical properties of the myelin sheaths. We discuss the implications of such changes for synaptic function and plasticity, and present the underlying mechanisms of neuron–glia communication, with a focus on glutamatergic signaling and the axomyelinic synapse. Finally, we examine evidence that myelin plasticity may be subject to critical periods. Taken together, the present review aims to provide insights into myelination in the context of brain circuit formation and function, emphasizing the bidirectional interplay between neurons and myelinating glial cells to better inform future investigations of nervous system plasticity

Neuroglial interactions underpinning myelin plasticity.

The CNS is extremely responsive to an ever-changing environment. Studies of neural circuit plasticity focus almost exclusively on functional and structural changes of neuronal synapses. In recent years, however, myelin plasticity has emerged as a potential modulator of neuronal networks. Myelination of previously unmyelinated axons and changes in the structure of myelin on already-myelinated axons (similar to changes in internode number and length or myelin thickness or geometry of the nodal area) can in theory have significant effects on the function of neuronal networks. In this article, the authors review the current evidence for myelin changes occurring in the adult CNS, highlight some potential underlying mechanisms of how neuronal activity may regulate myelin changes, and explore the similarities between neuronal and myelin plasticity. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 93-107, 2018.We would like to thank our funders: Lister Institute of Preventive Medicine: Ragnhildur Thóra Káradóttir; Allen Distinguished Investigator programme, through The Paul G. Allen Frontiers Group: Ragnhildur Thóra Káradóttir and Kimberley Evans; Biotechnology and Biological Sciences Research Council (BBSRC) and The Cambridge Trust: E. A. Claudia Pama; UK Multiple Sclerosis Society: Ragnhildur Thóra Káradóttir and Omar de-Faria-jr, Award number 50. The funders had no role in decision to publish, or preparation of the manuscript

Activity‐dependent alteration of early myelin ensheathment in a developing sensory circuit

Funder: Montreal Neurological Institute – University of Cambridge CollaborationFunder: Natural Sciences and Engineering Research Council of Canada; Id: http://dx.doi.org/10.13039/501100000038Abstract: Myelination allows for the regulation of conduction velocity, affecting the precise timing of neuronal inputs important for the development and function of brain circuits. In turn, myelination may be altered by changes in experience, neuronal activity, and vesicular release, but the links between sensory experience, corresponding neuronal activity, and resulting alterations in myelination require further investigation. We thus studied the development of myelination in the Xenopus laevis tadpole, a classic model for studies of visual system development and function because it is translucent and visually responsive throughout the formation of its retinotectal system. We begin with a systematic characterization of the timecourse of early myelin ensheathment in the Xenopus retinotectal system using immunohistochemistry of myelin basic protein (MBP) along with third harmonic generation (THG) microscopy, a label‐free structural imaging technique. Based on the mid‐larval developmental progression of MBP expression in Xenopus, we identified an appropriate developmental window in which to assess the effects of early temporally patterned visual experience on myelin ensheathment. We used calcium imaging of axon terminals in vivo to characterize the responses of retinal ganglion cells over a range of stroboscopic stimulation frequencies. Strobe frequencies that reliably elicited robust versus dampened calcium responses were then presented to animals for 7 d, and differences in the amount of early myelin ensheathment at the optic chiasm were subsequently quantified. This study provides evidence that it is not just the presence but also to the specific temporal properties of sensory stimuli that are important for myelin plasticity

Problems and Pitfalls of Identifying Remyelination in Multiple Sclerosis.

Regenerative medicines that promote remyelination in multiple sclerosis (MS) are making the transition from laboratory to clinical trials. While animal models provide the experimental flexibility to analyze mechanisms of remyelination, here we discuss the challenges in understanding where and how remyelination occurs in MS.The authors acknowledge the following support: The UK Multiple Sclerosis Society (RTK, CZ, RJMF), The Adelson Medical Research Foundation (DSR, DEB, RJMF), Intramural Research Program of NINDS/NIH (DSR), European Research Council (ERC) under the European Union Horizon 2020 Re- search and Innovation Program (RTK), The Lister Institute (RTK), and a core support grant from the Wellcome and MRC to the Wellcome-Medical Research Council Cambridge Stem Cell Institute (RTK, RJMF)

Oligodendrocyte Progenitor Cells Become Regionally Diverse and Heterogeneous with Age

We thank J. Trotter (Johannes Gutenberg University, Mainz, Germany) for the NG2-EYFP mice, Dr. Moritz Matthey for help with minipump transplantation, Miss Mariann Kovacs with embryonic dissection, and Dr. Katrin Volbracht for critical comments on the work. We acknowledge the support of the Wellcome – MRC Cambridge Stem Cell Institute core facility managers, in particular for this work Dr. Maike Paramor and Miss Victoria Murray with RNA-seq, and all staff members of the University Biomedical Services (UBS). This project has received the following funding: funding from the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Program (grant agreement 771411 to R.T.K. and K.A.E.), a Wellcome Trust research career development fellowship (091543/Z/10/Z to R.T.K. and K.A.E.) and studentship (102160/Z/13/Z to Y.K.), Paul G. Allen Frontiers Group Allen Distinguished Investigator Award 12076 (to R.T.K., D.K.-V., and K.A.E.), a Medical Research Council studentship (to S.O.S.), a Gates Cambridge Trust Gates scholarship (to S.S.), a Biotechnology and Biological Sciences Research Council studentship (to S.A.), a Homerton College Cambridge junior research fellowship (to D.K.-V.), UK MS Society Cambridge Myelin Repair Centre grant 50 (to R.T.K. and O.d.F.), a Fonds de Recherche du Québec - Santé scholarship (to Y.K.), a Cambridge Commonwealth, European and International Trust scholarship (to Y.K.), and a Lister Institute research prize (to R.T.K., K.A.E., and S.O.S.). Publisher Copyright: © 2018 The Author(s)Spitzer et al. show that oligodendrocyte progenitor cells (OPCs) acquire ion channels and sensitivity to neuronal activity that differ between region and age. The onset and decline of ion channels follow developmental milestones. This heterogeneity indicates different functional states of OPCs.Peer reviewe

Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations.

Tauopathies, such as Alzheimer's disease, some cases of frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy, are characterized by aggregates of the microtubule-associated protein tau, which are linked to neuronal death and disease development and can be caused by mutations in the MAPT gene. Six tau isoforms are present in the adult human brain and they differ by the presence of 3(3R) or 4(4R) C-terminal repeats. Only the shortest 3R isoform is present in foetal brain. MAPT mutations found in human disease affect tau binding to microtubules or the 3R:4R isoform ratio by altering exon 10 splicing. We have differentiated neurons from induced pluripotent stem cells derived from fibroblasts of controls and patients with N279K and P301L MAPT mutations. Induced pluripotent stem cell-derived neurons recapitulate developmental tau expression, showing the adult brain tau isoforms after several months in culture. Both N279K and P301L neurons exhibit earlier electrophysiological maturation and altered mitochondrial transport compared to controls. Specifically, the N279K neurons show abnormally premature developmental 4R tau expression, including changes in the 3R:4R isoform ratio and AT100-hyperphosphorylated tau aggregates, while P301L neurons are characterized by contorted processes with varicosity-like structures, some containing both alpha-synuclein and 4R tau. The previously unreported faster maturation of MAPT mutant human neurons, the developmental expression of 4R tau and the morphological alterations may contribute to disease development.This work was supported by CurePSP, The Cambridge Newton Trust, The William Scholl Foundation and the NIHR Cambridge Biomedical Research Centre (BRC). The contribution of the NC3Rs CRACK IT- Alzheimer’s Research UK is also acknowledged. S.A. holds a BBSRC studentship. A.G.-R. holds a Michael Foster Studentship. O.P. acknowledges BBSRC support. L.V. is supported by the ERC starting grant relieve-IMDs. S.O. and T.L. acknowledge support by the Irish Institute of Clinical Neuroscience. R.T.K. is supported by the Welcome Trust grant 091543/Z/10/Z and D.G. and M.dC.V.-H. are supported by Wellcome Trust grant #098051.This is the final version. It was first published by OUP at http://dx.doi.org/10.1093/brain/awv22

Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer's disease via MFG-E8

Synapse loss correlates with cognitive decline in Alzheimer's disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared with non-disease controls, and that proximity to amyloid-β plaques and the APOE4 risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting interactions of MFG-E8 rescues the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells at least in part via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation.</p

Functional implication for myelin regeneration in recovery from ischaemic stroke.

This scientific commentary refers to ‘Prolonged myelin deficits contribute to neuron loss and functional impairments after ischaemic stroke’ by Cheng et al. (https://doi.org/10.1093/brain/awae029)