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KIF2C Regulates Synaptic Plasticity and Cognition by Mediating bioRxiv preprint doi: https://doi.org/10.1101/2021.08.05.455197; this version posted August 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 KIF2C regulates synaptic plasticity and cognition by mediating 2 dynamic microtubule invasion of dendritic spines 3 Rui Zheng1,2†, Yong-Lan Du1,2†, Xin-Tai Wang2, Tai-Lin Liao1,2, Zhe Zhang1,2, Na Wang1,2, Xiu- 4 Mao Li3, Ying Shen4, Lei Shi5, Jian-Hong Luo1,2*, Jun Xia6*, Ziyi Wang7*, Junyu Xu1,2* 5 6 1Department of Neurobiology and Department of Rehabilitation of the Children’s 7 Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China. 8 2NHC and CAMS Key Laboratory of Medical Neurobiology, Ministry of Education Frontier 9 Science Center for Brain Research and Brain Machine Integration, School of Brain Science and 10 Brain Medicine, Zhejiang University, Hangzhou, 310058, China. 11 3Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School 12 of Medicine, Hangzhou, 310058, China. 13 4Department of Physiology and Department of Neurology of First Affiliated Hospital, Zhejiang 14 University School of Medicine, Hangzhou, 310058, China. 15 5JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research, Jinan University, 16 Guangzhou, China. 17 6Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong 18 University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China. 19 7Innovative Institute of Basic Medical Sciences of Zhejiang University (Yuhang), Hangzhou, 20 310012, China. 21 †These authors contributed equally to this work. 22 *Corresponding author. Junyu Xu ([email protected]), Ziyi Wang ([email protected]), Jun Xia 23 ([email protected]) and Jian-Hong Luo ([email protected]). 24 bioRxiv preprint doi: https://doi.org/10.1101/2021.08.05.455197; this version posted August 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 25 Abstract 26 Dynamic microtubules play a critical role in cell structure and function. In nervous 27 system, microtubules specially extend into and out of synapses to regulate synaptic 28 development and plasticity. However, the detailed polymerization especially the 29 depolymerization mechanism that regulates dynamic microtubules in synapses is still 30 unclear. In this study, we find that KIF2C, a dynamic microtubule depolymerization 31 protein without known function in the nervous system, plays a vital role in the 32 structural and functional plasticity of synapses and regulates cognitive function. 33 Using RNAi knockdown and conditional knockout approaches, we showed that 34 KIF2C regulates spine morphology and synaptic membrane expression of AMPA (α- 35 amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptors. Moreover, KIF2C 36 deficiency leads to impaired excitatory transmission, long-term potentiation, and 37 altered cognitive behaviors in mice. Mechanistically, KIF2C regulates microtubule 38 dynamics and microtubule invasion of spines in neurons by its microtubule 39 depolymerization capability in a neuronal activity-dependent manner. This study 40 explores a novel function of KIF2C in the nervous system and provides an important 41 regulatory mechanism on how microtubule invasion of spines regulates synaptic 42 plasticity and cognition behaviors. 43 Keywords: KIF2C, microtubule depolymerization, spine invasion, long-term 44 potentiation, cognition 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.08.05.455197; this version posted August 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 45 Introduction 46 Microtubules (MTs) are eukaryotic cytoskeletons that play an important role in cell 47 function. In the central nervous system, MTs serve as a structural basis for trafficking 48 material throughout the neuron and are the primary regulators of neuronal 49 differentiation (1). The MTs dynamic instability, i.e. the growing or shrinking of MT 50 plus end, has been detected in both shaft and dendritic protrusions (2) and is involved 51 in spine formation and synaptic function (3-6). Inhibition of MT polymerization results 52 in deficits in LTP and negatively affects memory formation or retention (7, 8). The 53 abnormal MTs dynamics is associated with several neurodegenerative and psychiatric 54 diseases, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, and 55 depression (9). During neuronal activities, microtubules can be regulated to extend from 56 the dendritic shaft into spines and affect synaptic structure and function (3-8), which 57 could be an important event for synaptic plasticity. However, regulatory mechanism 58 underlying microtubule dynamics in or out from synapse upon neuronal activity is still 59 unclear, nor its role in learning and memory. 60 The polymerization dynamics of MTs are essential for their biological functions 61 and can be regulated by many MT-associated proteins (MAPs) (10, 11). The kinesin-13 62 family of kinesin superfamily proteins (KIFs) has a distinct function in depolymerizing 63 MTs (12), and therefore is involved in many MT-dependent events (13, 14). KIF2C, 64 also called mitotic centromere-associated kinesin (MCAK), is the best-characterized 65 family member and is localized to the spindle poles, spindle midzone, and kinetochores 66 in dividing cells. KIF2C utilizes MT depolymerase activity to regulate spindle 67 formation and correct inappropriate MT attachments at kinetochores (15-17). KIF2C 68 uses ATP hydrolysis for MT depolymerization from both ends and directly interacts 69 with EBs to enhance its destabilizing ability (18-22). Particularly, KIF2C is associated 70 with Alzheimer’s disease and suicidality psychiatric disorders. In vitro study showed 71 that Oligomeric amyloid-β (Aβ) directly inhibits the MT-dependent ATPase activity of 72 KIF2C and leads to abnormal mitotic spindles, which may cause chromosome mis- 73 segregation and increased aneuploid neurons and thereby contributes to the 74 development of Alzheimer’s disease (23). Clinical evidence shows that KIF2C is 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.08.05.455197; this version posted August 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 75 significantly decreased in suicidal ideation cohort and could be utilized as a reference 76 for predicting suicidality (24). However, the in vivo physiological function of KIF2C in 77 the central nervous system (CNS) remains to be elucidated. 78 In this study, we have found that KIF2C in the CNS is expressed in a brain-wide 79 and synaptic localized pattern, which could be regulated by neuronal activity. Using a 80 nervous system-specific KIF2C conditional knockout (cKO) mouse, we further 81 confirmed its pivotal role in spine morphology, synaptic transmission, and synaptic 82 plasticity. By overexpression of KIF2C wild-type (WT) and MT depolymerization- 83 defective mutation, we have found that KIF2C regulates synaptic plasticity by 84 mediating MT depolymerization and affecting MT synaptic invasion. Furthermore, 85 KIF2C cKO mice exhibit deficiencies in multiple cognition-associated tasks, which 86 could be rescued by overexpression of KIF2C WT but not the MT depolymerization- 87 defective mutant. Overall, our study explores a novel function of KIF2C in neurons and 88 synaptic plasticity, and reveals how MT dynamics in synapses upon neuronal activity 89 contributes to cognition. 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.08.05.455197; this version posted August 5, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 90 Results 91 KIF2C is highly expressed in the brain and at the synapse 92 Previous studies have showed that KIF2C plays an important role during cell division 93 in mitotic cells (25-27); however, it is not clear whether KIF2C is also present in the 94 nervous system. Western blot analyses showed that KIF2C was expressed in multiple 95 regions of the brain (Figure 1A), and shows sustained high expression in the 96 hippocampus throughout the postnatal stages (Figure 1B). To identify KIF2C 97 abundance in neurons, western blot analyses were performed on whole-cell extracts of 98 cultured hippocampal neurons (Figure 1C). The results showed that KIF2C was 99 expressed in a development-related pattern in cultured neurons: detectable at day in 100 vitro 3 (DIV 3) and significantly increased at DIV 10. Moreover, the subcellular 101 fractionation analysis showed an enrichment of KIF2C in the postsynaptic density (PSD) 102 fraction (Figure 1D). Immunofluorescent staining of cultured neurons revealed KIF2C 103 expression as granular puncta of different sizes along dendrites overlapping with the 104 postsynaptic marker PSD-95 and presynaptic protein Bassoon (Figure 1E). These 105 results showed that KIF2C is abundantly expressed in CNS neurons and is enriched at 106 postsynaptic density, suggesting a possible function in synapses. 107 KIF2C knockdown affects spine morphology, synaptic transmission and long- 108 term potentiation in vitro and in vivo 109 To explore the function of KIF2C in synapses, KIF2C was knocked down in cultured 110 hippocampal neurons using viral-mediated KIF2C shRNA (shKIF2C) (Figure 2A) at 111 DIV 7–10 and the spine morphology was examined at DIV 16–18. The results showed 112 that KIF2C knockdown did not affect spine density (Figure 2B).
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