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Neuron. 2018 Aug 22;99(4):689-701.e5. doi: 10.1016/j.neuron.2018.07.017. Epub 2018 Aug 2.

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

Author information

1
Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China.
2
Department of Physiology, Third Military Medical University, Chongqing 400038, China.
3
Department of Digital Medicine, Biomedical Engineering College, Third Military Medical University, Chongqing 400038, China.
4
Department of Pathology, Affiliated Xinqiao Hospital, Third Military Medical University, Chongqing 400038, China.
5
UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA.
6
Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China. Electronic address: xiaolan35@hotmail.com.
7
UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: jonah.chan@ucsf.edu.
8
Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing 400038, China. Electronic address: meif@tmmu.edu.cn.

Abstract

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.

KEYWORDS:

M1R; Olig2; U-50488; beam-walking test; clemastine; hypomyelination; kappa opioid receptor; synaptogenesis; vGlut1; white matter injury

PMID:
30078577
PMCID:
PMC6170028
DOI:
10.1016/j.neuron.2018.07.017
[Indexed for MEDLINE]
Free PMC Article

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