4.7 Article

Insufficient Oligodendrocyte Turnover in Optic Nerve Contributes to Age-Related Axon Loss and Visual Deficits

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JOURNAL OF NEUROSCIENCE
卷 43, 期 11, 页码 1859-1870

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SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2130-22.2023

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clemastine; myelin; myelination; oligodendrogenesis; OPC; RGC

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Age-related decline in visual functions is a common health problem among elderly people, but there are currently no effective therapies available. The degeneration of axons and loss of myelin in optic nerves are age-dependent and result in functional deficits. Oligodendrocyte turnover in adult optic nerves is actively ongoing, but the longitudinal change and functional significance of this turnover in aging optic nerves remain largely unknown.
Age-related decline in visual functions is a prevalent health problem among elderly people, and no effective therapies are available up-to-date. Axon degeneration and myelin loss in optic nerves (ONs) are age-dependent and become evident in middle-aged (13-18 months) and old (20-22 months) mice of either sex compared with adult mice (3-8 months), accompanied by functional deficits. Oligodendrocyte (OL) turnover is actively going on in adult ONs. However, the longitudinal change and functional significance of OL turnover in aging ONs remain largely unknown. Here, using cell-lineage labeling and tracing, we reported that oligodendrogenesis dis-played an age-dependent decrease in aging ONs. To understand whether active OL turnover is required for maintaining axons and visual function, we conditionally deleted the transcription factor Olig2 in the oligodendrocyte precursor cells of young mice. Genetically dampening OL turnover by Olig2 ablation resulted in accelerated axon loss and retinal degeneration, and subsequently impaired ON signal transmission, suggesting that OL turnover is an important mechanism to sustain axon survival and visual func-tion. To test whether enhancing oligodendrogenesis can prevent age-related visual deficits, 12-month-old mice were treated with clem-astine, a pro-myelination drug, or induced deletion of the muscarinic receptor 1 in oligodendrocyte precursor cells. The clemastine treatment or muscarinic receptor 1 deletion significantly increased new OL generation in the aged ONs and consequently preserved visual function and retinal integrity. Together, our data indicate that dynamic OL turnover in ONs is required for axon survival and visual function, and enhancing new OL generation represents a potential approach to reversing age-related declines of visual function.

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