Journal Club (March 14, 2022)

eLife 2022;11:e72483 DOI: 10.7554/eLife.72483

KIF2C regulates synaptic plasticity and cognition in mice through dynamic microtubule depolymerization (KIF2Cは動的微小管解重合を介してマウスのシナプス可塑性と認知を調節する)

Rui ZhengYonglan DuXintai WangTailin LiaoZhe ZhangNa WangXiumao LiYing ShenLei ShiJianhong Luo 

Department of Neurobiology and Department of Rehabilitation of the Children’s Hospital, Zhejiang University School of Medicine, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Ministry of Education Frontier Science Center for Brain Research and Brain Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, China; 浙江大学

Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, China; Department of Physiology and Department of Neurology of First Affiliated Hospital, Zhejiang University School of Medicine, China; 

JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, Jinan University, China; Division of Life Science and The Brain and Intelligence Research Institute, The Hong Kong University of Science and Technology, China; Innovative Institute of Basic Medical Sciences of Zhejiang University (Yuhang), China


Dynamic microtubules play a critical role in cell structure and function. In nervous system, microtubules are the major route for cargo protein trafficking and they specially extend into and out of synapses to regulate synaptic development and plasticity. However, the detailed depolymerization mechanism that regulates dynamic microtubules in synapses and dendrites is still unclear. In this study, we find that KIF2C, a dynamic microtubule depolymerization protein without known function in the nervous system, plays a pivotal role in the structural and functional plasticity of synapses and regulates cognitive function in mice. Through its microtubule depolymerization capability, KIF2C regulates microtubule dynamics in dendrites, and regulates microtubule invasion of spines in neurons in a neuronal activity-dependent manner. Using RNAi knockdown and conditional knockout approaches, we showed that KIF2C regulates spine morphology and synaptic membrane expression of AMPA receptors. Moreover, KIF2C deficiency leads to impaired excitatory transmission, long-term potentiation, and altered cognitive behaviors in mice. Collectively, our study explores a novel function of KIF2C in the nervous system and provides an important regulatory mechanism on how activity-dependent microtubule dynamic regulates synaptic plasticity and cognition behaviors.


Editor’s evaluation

In this manuscript, the authors report a set of exciting and novel data suggesting a critical role of the microtubule depolymerizing kinesin-13 KIF2C/MCAK in glutamate receptor trafficking, synaptic plasticity and behaviours related to learning and memory. The authors use multiple experimental approaches, ranging from electron microscopy to mouse behavioral analysis to support the conclusions, which are convincing and provide novel insights into the in vivo functions of KIF2C in the regulation of excitatory synaptic structure and function and cognitive behaviors.


xpression of KIF2C in the central nervous system.
(A) Expression of KIF2C in different mouse brain regions by immunoblotting. (B) Expression of KIF2C and EB3 in mouse hippocampus at different day in vitro. (C) Developmental expression patterns of KIF2C and EB3 in cultured hippocampal neurons. (D) Subcellular distribution of KIF2C in mouse hippocampus. H, homogenate; S1, low-speed supernatant; P1, nuclei; S2, microsomal fraction; P2, synaptosomal fraction; S3, presynaptosomal fraction; P3, postsynaptic density and synapto, synaptophysin. (E) Representative images of hippocampal neurons double-labeled with antibodies against KIF2C, PSD-95 (postsynaptic marker) and Bassoon (presynaptic marker). Scale bar, 5 μm.
KIF2C displays translocation after cLTP and is required for synaptic structure plasticity.
(A) Electrophoresis of kif2c and gapdh amplicons from individual control and shkif2c hippocampal neurons. Histograms show percentage changes of kif2c mRNA levels (% of control, **p < 0.01, n = 6, Student’s t-test). (B) Cultured hippocampal neurons were infected by control shRNA and shkif2c lentivirus at DIV 7–10, and captured at DIV 18–20. GFP was used to label neuron volume. Scale bar, 1 μm. Spine number per 1 μm (right), n = 20 neurons from three independent culture. Student’s t-test. (C–E) Cultured hippocampal neurons were infected by control shRNA and shkif2c lentivirus at DIV 7–10, and incubated with ECS or glycine (200 μM) for 10 min at DIV 18–20. Scale bar, 1 μm. Spine density (D) and spine head width (E) are calculated. Spine density, n = 17 neurons from three independent culture. Spine head width, n = 24 neurons from three independent culture. n.s., p > 0.05, *p < 0.05, ****p < 0.0001; One way-ANOVA for spine density and head width (post hoc comparison).(F) Subcellular fraction of KIF2C in cultured hippocampus neurons after 10 min of glycine treatment. N-cadherin (N-cad) was served as negative control. H, Homogenate; S2, microsomal fraction; P2, synaptosomal fraction and P3, postsynaptic density from ECS and cLTP treated neurons. (G) Quantification of KIF2C and β-tubulin accumulation with or without cLTP treatment in each fraction. *p < 0.05, **p < 0.01; Student’s t-test, n = 7 experimental repeats. (H) Representative images of co-localization of KIF2C (red), PSD-95 (green), and Microtubule associated protein 2 (MAP2) (blue). Scale bar, 1 μm. (I) The percentage of KIF2C puncta that were colocalized with PSD-95 puncta decreased after cLTP treatment. n = 20 neurons from three cultures. n.s., p > 0.05, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001; Student’s t-test.


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