Calcineurin Signaling Mediates Disruption of the Axon Initial Segment Cytoskeleton after Injury
Yanan Zhao,
Xuanyuan Wu,
Xin Chen,
Jianan Li,
Cuiping Tian,
Jiangrui Chen,
Cheng Xiao,
Guisheng Zhong,
Shuijin He
Affiliations
Yanan Zhao
School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Pudong New District, Shanghai 201210, China
Xuanyuan Wu
School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Pudong New District, Shanghai 201210, China
Xin Chen
School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Pudong New District, Shanghai 201210, China
Jianan Li
School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Pudong New District, Shanghai 201210, China
Cuiping Tian
iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Pudong New District, Shanghai 201210, China
Jiangrui Chen
School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Pudong New District, Shanghai 201210, China; Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China
Cheng Xiao
School of Anesthesiology, Xuzhou Medical University, 209 Tongshan Road, KJL-D423, Xuzhou, Jiangsu Province 221004, China
Guisheng Zhong
School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Pudong New District, Shanghai 201210, China; iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Pudong New District, Shanghai 201210, China; Corresponding author
Shuijin He
School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Pudong New District, Shanghai 201210, China; Corresponding author
Summary: 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 Nav1.6 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 Nav1.6 following injury, indicating that neurofascin is required for Nav1.6 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. : Neuroscience; Molecular Neuroscience; Cellular Neuroscience Subject Areas: Neuroscience, Molecular Neuroscience, Cellular Neuroscience
