Enhancing Oligodendrocyte Myelination Rescues Synaptic Loss and Improves Functional Recovery after Chronic Hypoxia

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.

[1]  Ben A. Barres,et al.  Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner , 2012, Neuron.

[2]  Klaus-Armin Nave,et al.  Myelination and the trophic support of long axons , 2010, Nature Reviews Neuroscience.

[3]  John L. Robinson,et al.  TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss , 2017, Neuron.

[4]  E. Ullian,et al.  Dynamic Modulation of Myelination in Response to Visual Stimuli Alters Optic Nerve Conduction Velocity , 2016, The Journal of Neuroscience.

[5]  R. Henry,et al.  Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury , 2018, Brain : a journal of neurology.

[6]  Susumu Tonegawa,et al.  Presynaptic m1 muscarinic receptors are necessary for mGluR long-term depression in the hippocampus , 2010, Proceedings of the National Academy of Sciences.

[7]  Kevin W. Kelley,et al.  Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development , 2018, Science.

[8]  David J. Anderson,et al.  The bHLH Transcription Factor Olig2 Promotes Oligodendrocyte Differentiation in Collaboration with Nkx2.2 , 2001, Neuron.

[9]  Ramgopal Venkataraman,et al.  Perinatal chronic hypoxia induces cortical inflammation, hypomyelination, and peripheral myelin‐specific T cell autoreactivity , 2016, Journal of leukocyte biology.

[10]  B. Richardson,et al.  Synaptic Development and Neuronal Myelination Are Altered with Growth Restriction in Fetal Guinea Pigs , 2014, Developmental Neuroscience.

[11]  Xiaoqin Zhu,et al.  Age-dependent fate and lineage restriction of single NG2 cells , 2011, Development.

[12]  S. Hauser,et al.  Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial , 2017, The Lancet.

[13]  Y. Dan,et al.  Spike timing-dependent plasticity: a Hebbian learning rule. , 2008, Annual review of neuroscience.

[14]  Monica Luciana,et al.  Cognitive development in children born preterm: Implications for theories of brain plasticity following early injury , 2003, Development and Psychopathology.

[15]  C. Tohda,et al.  Learning Deficits and Agenesis of Synapses and Myelinated Axons in Phosphoinositide-3 Kinase-Deficient Mice , 2007, Neurosignals.

[16]  J. Kiss,et al.  Process of cortical network formation and impact of early brain damage. , 2014, Current opinion in neurology.

[17]  L. Wrabetz,et al.  Signals to promote myelin formation and repair , 2010, Nature Reviews Neurology.

[18]  F. Vaccarino,et al.  Neurobiology of premature brain injury , 2014, Nature Neuroscience.

[19]  Changsheng Du,et al.  Kappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination , 2016, Nature Communications.

[20]  E. Huang,et al.  Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination , 2011, Nature Neuroscience.

[21]  László Négyessy,et al.  Ablation of TNAP function compromises myelination and synaptogenesis in the mouse brain , 2012, Cell and Tissue Research.

[22]  F. Gage,et al.  A regenerative approach to the treatment of multiple sclerosis , 2013, Nature.

[23]  D. Lorrain,et al.  Identification of the Kappa-Opioid Receptor as a Therapeutic Target for Oligodendrocyte Remyelination , 2016, The Journal of Neuroscience.

[24]  D. Holtzman,et al.  Selective Vulnerability of Late Oligodendrocyte Progenitors to Hypoxia–Ischemia , 2002, The Journal of Neuroscience.

[25]  P. Ballabh,et al.  Intraventricular Hemorrhage in Premature Infants: Mechanism of Disease , 2010, Pediatric Research.

[26]  J. Chan,et al.  Remodeling myelination: implications for mechanisms of neural plasticity , 2016, Nature Neuroscience.

[27]  J DeFelipe,et al.  Postnatal development of the vesicular gaba transporter in rat cerebral cortex , 2003, Neuroscience.

[28]  V. Gallo,et al.  GABAergic regulation of cerebellar NG2-cell development is altered in perinatal white matter injury , 2015, Nature Neuroscience.

[29]  C. Nelson,et al.  Neurobehavioural functioning in neonatal intensive care unit graduates in late childhood and early adolescence. , 2002, Brain : a journal of neurology.

[30]  P. Davis,et al.  Prophylactic indomethacin for preterm infants: a systematic review and meta-analysis , 2003, Archives of disease in childhood. Fetal and neonatal edition.

[31]  Steven P. Miller,et al.  Rodent Hypoxia–Ischemia Models for Cerebral Palsy Research: A Systematic Review , 2016, Front. Neurol..

[32]  D. Linden,et al.  Homer Binds a Novel Proline-Rich Motif and Links Group 1 Metabotropic Glutamate Receptors with IP3 Receptors , 1998, Neuron.

[33]  D. Lorrain,et al.  Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery , 2016, eLife.

[34]  T. Inder,et al.  Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. , 2006, The New England journal of medicine.

[35]  Stephen L Hauser,et al.  Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis , 2014, Nature Medicine.

[36]  S. Back,et al.  Arrested oligodendrocyte lineage maturation in chronic perinatal white matter injury , 2008, Annals of neurology.

[37]  F. Hyder,et al.  Intranasal epidermal growth factor treatment rescues neonatal brain injury , 2013, Nature.

[38]  S. Back.  White matter injury in the preterm infant: pathology and mechanisms , 2017, Acta Neuropathologica.

[39]  J. Chan,et al.  Stage-Specific Deletion of Olig2 Conveys Opposing Functions on Differentiation and Maturation of Oligodendrocytes , 2013, The Journal of Neuroscience.

[40]  W. Stewart,et al.  Disrupted synaptic development in the hypoxic newborn brain , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. Rowitch,et al.  Oligodendrocyte-Encoded HIF Function Couples Postnatal Myelination and White Matter Angiogenesis , 2014, Cell.

[42]  Steven P. Miller,et al.  Arrested preoligodendrocyte maturation contributes to myelination failure in premature infants , 2012, Annals of neurology.

[43]  K. Ligon,et al.  RESEARCH ARTICLE: Myelin Abnormalities without Oligodendrocyte Loss in Periventricular Leukomalacia , 2008, Brain pathology.

[44]  V. Gallo,et al.  A functional role for EGFR signaling in myelination and remyelination , 2007, Nature Neuroscience.

[45]  H. Sarnat,et al.  Synaptogenesis and Myelination in the Nucleus/Tractus Solitarius , 2016, Journal of child neurology.

[46]  E. Huang,et al.  Parallel states of pathological Wnt signaling in neonatal brain injury and colon cancer , 2014, Nature Neuroscience.

[47]  Ben Grayson,et al.  Assessment of disease-related cognitive impairments using the novel object recognition (NOR) task in rodents , 2015, Behavioural Brain Research.

[48]  Justin Dean,et al.  Histopathological correlates of magnetic resonance imaging–defined chronic perinatal white matter injury , 2011, Annals of neurology.

[49]  K. Nave,et al.  Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination , 2003, Nature Genetics.

[50]  Jeanne T Paz,et al.  Focal Cortical Infarcts Alter Intrinsic Excitability and Synaptic Excitation in the Reticular Thalamic Nucleus , 2010, The Journal of Neuroscience.

[51]  B. Barres,et al.  The role of glial cells in synapse elimination , 2012, Current Opinion in Neurobiology.

[52]  S. Dunnett,et al.  Tests to assess motor phenotype in mice: a user's guide , 2009, Nature Reviews Neuroscience.

[53]  D. Ferriero,et al.  The role of inflammation in perinatal brain injury , 2015, Nature Reviews Neurology.

[54]  S. Back,et al.  Pathophysiology of glia in perinatal white matter injury , 2014, Glia.

[55]  X. Wei,et al.  Timing in neural maturation: arrest, delay, precociousness, and temporal determination of malformations. , 2015, Pediatric neurology.

[56]  J. Rothstein,et al.  Oligodendroglia: metabolic supporters of axons. , 2013, Trends in cell biology.

[57]  S. Back.  Brain Injury in the Preterm Infant: New Horizons for Pathogenesis and Prevention. , 2015, Pediatric neurology.

[58]  J. Volpe,et al.  Neurobiology of Periventricular Leukomalacia in the Premature Infant , 2001, Pediatric Research.

[59]  Ann-Beth Moller,et al.  National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications , 2012, The Lancet.

[60]  D. Ferriero.  Neonatal brain injury. , 2004, The New England journal of medicine.

[61]  P. Greengard,et al.  Synapsin I (Protein I), a nerve terminal-specific phosphoprotein. II. Its specific association with synaptic vesicles demonstrated by immunocytochemistry in agarose-embedded synaptosomes , 1983, The Journal of cell biology.

[62]  Responses of Rat Brain Interneuronal Synapses to Hypoxia in the Early Neonatal Period , 2014, Neuroscience and Behavioral Physiology.

[63]  Y. Dan,et al.  Spike Timing-Dependent Plasticity of Neural Circuits , 2004, Neuron.

[64]  Reint K Jellema,et al.  White matter injury following fetal inflammatory response syndrome induced by chorioamnionitis and fetal sepsis: lessons from experimental ovine models. , 2012, Early human development.

[65]  J. Chan,et al.  Regulation and dysregulation of axon infrastructure by myelinating glia , 2017, The Journal of cell biology.

[66]  H. Hida,et al.  Dysfunction in Motor Coordination in Neonatal White Matter Injury Model without Apparent Neuron Loss , 2016, Cell transplantation.

[67]  L. Parada,et al.  A Critical Role for Dorsal Progenitors in Cortical Myelination , 2006, The Journal of Neuroscience.

[68]  Daniel R. Berger,et al.  Distinct Profiles of Myelin Distribution Along Single Axons of Pyramidal Neurons in the Neocortex , 2014, Science.

[69]  John L. Robinson,et al.  TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss , 2017, Neuron.

[70]  W. Deng,et al.  The vulnerability of thalamocortical circuitry to hypoxic-ischemic injury in a mouse model of periventricular leukomalacia , 2016, BMC Neuroscience.

[71]  Daniel J. Flannery,et al.  Outcomes in young adulthood for very-low-birth-weight infants. , 2002, The New England journal of medicine.