An active vesicle priming machinery suppresses axon regeneration upon adult CNS injury

被引:50
作者
Hilton, Brett J. [1 ]
Husch, Andreas [1 ]
Schaffran, Barbara [1 ]
Lin, Tien-chen [1 ]
Burnside, Emily R. [1 ]
Dupraz, Sebastian [1 ]
Schelski, Max [1 ]
Kim, Jisoo [1 ,2 ,3 ]
Mueller, Johannes Alexander [4 ]
Schoch, Susanne [4 ]
Imig, Cordelia [5 ,6 ]
Brose, Nils [5 ]
Bradke, Frank [1 ]
机构
[1] German Ctr Neurodegenerat Dis DZNE, Lab Axonal Growth & Regenerat, Venusberg Campus 1-99, D-53127 Bonn, Germany
[2] Harvard Univ, Ctr Brain Sci, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA
[3] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA
[4] Univ Bonn, Med Fac, Inst Neuropathol, D-53105 Bonn, Germany
[5] Max Planck Inst Expt Med, Dept Mol Neurobiol, D-37075 Gottingen, Germany
[6] Univ Copenhagen, Dept Neurosci, DK-2200 Copenhagen, Denmark
关键词
PERIPHERAL NERVOUS-SYSTEM; ROOT GANGLION NEURONS; GROWTH CONE MOTILITY; CALCIUM REGULATION; SYNAPTIC TRANSMISSION; INTRATHECAL BACLOFEN; NEURITE ELONGATION; RELEASE; FUSION; SYNAPTOGENESIS;
D O I
10.1016/j.neuron.2021.10.007
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Axons in the adult mammalian central nervous system fail to regenerate after spinal cord injury. Neurons lose their capacity to regenerate during development, but the intracellular processes underlying this loss are unclear. We found that critical components of the presynaptic active zone prevent axon regeneration in adult mice. Transcriptomic analysis combined with live-cell imaging revealed that adult primary sensory neurons downregulate molecular constituents of the synapse as they acquire the ability to rapidly grow their axons. Pharmacogenetic reduction of neuronal excitability stimulated axon regeneration after adult spinal cord injury. Genetic gain-and loss-of-function experiments uncovered that essential synaptic vesicle priming proteins of the presynaptic active zone, but not clostridial-toxin-sensitive VAMP-family SNARE proteins, inhibit axon regeneration. Systemic administration of Baclofen reduced voltage-dependent Ca2+ influx in primary sensory neurons and promoted their regeneration after spinal cord injury. These findings indicate that functional presynaptic active zones constitute a major barrier to axon regeneration.
引用
收藏
页码:51 / +
页数:27
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