Calcineurin Signaling Mediates Disruption of the Axon Initial Segment Cytoskeleton after Injury

被引:7
|
作者
Zhao, Yanan [1 ]
Wu, Xuanyuan [1 ]
Chen, Xin [1 ]
Li, Jianan [1 ]
Tian, Cuiping [2 ]
Chen, Jiangrui [1 ,3 ,4 ]
Xiao, Cheng [5 ]
Zhong, Guisheng [1 ,2 ]
He, Shuijin [1 ]
机构
[1] ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China
[2] ShanghaiTech Univ, Human Inst, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China
[3] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Neurosci, Shanghai, Peoples R China
[4] Univ Chinese Acad Sci, Beijing, Peoples R China
[5] Xuzhou Med Univ, Sch Anesthesiol, 209 Tongshan Rd,KJL-D423, Xuzhou 221004, Jiangsu, Peoples R China
基金
中国国家自然科学基金;
关键词
ACTIVITY-DEPENDENT RELOCATION; ACTION-POTENTIAL INITIATION; DAMAGE; VULNERABILITY; NEUROFASCIN; HIPPOCAMPUS; INHIBITION; MECHANISMS; PLASTICITY; ISCHEMIA;
D O I
10.1016/j.isci.2020.100880
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The axon initial segment (AIS) cytoskeleton undergoes rapid and irreversible disruption prior to cell death after injury, and loss of AIS integrity can produce profound neurological effects on the nervous system. Here we described a previously unrecognized mechanism for ischemia-induced alterations in AIS integrity. We show that in hippocampal CA1 pyramidal neurons Na v 1.6 mostly preserves at the AIS after disruption of the cytoskeleton in a mouse model of middle cerebral artery occlusion. Genetic removal of neurofascin-186 leads to rapid disruption of Na(v)1.6 following injury, indicating that neurofascin is required for Na(v)1.6 maintenance at the AIS after cytoskeleton collapse. Importantly, calcineurin inhibition with FK506 fully protects AIS integrity and sufficiently prevents impairments of spatial learning and memory from injury. This study provides evidence that calcineurin activation is primarily involved in initiating disassembly of the AIS cytoskeleton and that maintaining AIS integrity is crucial for therapeutic strategies to facilitate recovery from injury.
引用
收藏
页数:40
相关论文
共 50 条
  • [21] Functional implications of axon initial segment cytoskeletal disruption in stroke (vol 37, pg 75, 2016)
    Stoler, Ohad
    Fleidervish, Ilya A.
    ACTA PHARMACOLOGICA SINICA, 2016, 37 (07) : 1012 - 1012
  • [22] Remodeling of the Axon Initial Segment After Focal Cortical and White Matter Stroke
    Hinman, Jason D.
    Rasband, Matthew N.
    Carmichael, S. Thomas
    STROKE, 2013, 44 (01) : 182 - 189
  • [23] Wnt-Ryk Signaling Mediates Axon Growth Inhibition and Limits Functional Recovery after Spinal Cord Injury
    Miyashita, Tomohiro
    Koda, Masao
    Kitajo, Keiko
    Yamazaki, Masashi
    Takahashi, Kazuhisa
    Kikuchi, Akira
    Yamashita, Toshihide
    JOURNAL OF NEUROTRAUMA, 2009, 26 (07) : 955 - 964
  • [24] Inhibitory Injury Signaling Represses Axon Regeneration After Dorsal Root Injury
    Fernando M. Mar
    Anabel R. Simões
    Inês S. Rodrigo
    Mónica M. Sousa
    Molecular Neurobiology, 2016, 53 : 4596 - 4605
  • [25] Inhibitory Injury Signaling Represses Axon Regeneration After Dorsal Root Injury
    Mar, Fernando M.
    Simoes, Anabel R.
    Rodrigo, Ines S.
    Sousa, Monica M.
    MOLECULAR NEUROBIOLOGY, 2016, 53 (07) : 4596 - 4605
  • [26] THE EFFECT OF MILD TRAUMATIC BRAIN INJURY (MTBI) ON THE STRUCTURAL PLASTICITY OF THE AXON INITIAL SEGMENT (AIS)
    Vascak, Michal
    Baer, Matthew L.
    Povlishock, John T.
    JOURNAL OF NEUROTRAUMA, 2015, 32 (12) : A42 - A42
  • [27] Mild traumatic brain injury in the mouse induces axotomy primarily within the axon initial segment
    John E. Greer
    Anders Hånell
    Melissa J. McGinn
    John T. Povlishock
    Acta Neuropathologica, 2013, 126 : 59 - 74
  • [28] Mild traumatic brain injury in the mouse induces axotomy primarily within the axon initial segment
    Greer, John E.
    Hanell, Anders
    McGinn, Melissa J.
    Povlishock, John T.
    ACTA NEUROPATHOLOGICA, 2013, 126 (01) : 59 - 74
  • [29] THE EFFECT OF MILD TRAUMATIC BRAIN INJURY (MTBI) ON THE STRUCTURAL PLASTICITY OF THE AXON INITIAL SEGMENT (AIS)
    Vascak, Michal
    Hanell, Anders
    Greer, John E.
    Jacobs, Kimberle M.
    Povlishock, John T.
    JOURNAL OF NEUROTRAUMA, 2014, 31 (05) : A65 - A65
  • [30] Increased thrombospondin-4 after nerve injury mediates disruption of intracellular calcium signaling in primary sensory neurons
    Guo, Yuan
    Zhang, Zhiyong
    Wu, Hsiang-en
    Luo, Z. David
    Hogan, Quinn H.
    Pan, Bin
    NEUROPHARMACOLOGY, 2017, 117 : 292 - 304