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Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice.
EMBO J 2020; 39(1):e101090EJ

Abstract

The transport of N-methyl-d-aspartate receptors (NMDARs) is crucial for neuronal plasticity and synapse formation. Here, we show that KIF3B, a member of the kinesin superfamily proteins (KIFs), supports the transport of vesicles simultaneously containing NMDAR subunit 2A (NR2A) and the adenomatous polyposis coli (APC) complex. Kif3b+/- neurons exhibited a reduction in dendritic levels of both NR2A and NR2B due to the impaired transport of NR2A and increased degradation of NR2B. In Kif3b+/- hippocampal slices, electrophysiological NMDAR response was found decreased and synaptic plasticity was disrupted, which corresponded to a common feature of schizophrenia (SCZ). The histological features of Kif3b+/- mouse brain also mimicked SCZ features, and Kif3b+/- mice exhibited behavioral defects in prepulse inhibition (PPI), social interest, and cognitive flexibility. Indeed, a mutation of KIF3B was specifically identified in human SCZ patients, which was revealed to be functionally defective in a rescue experiment. Therefore, we propose that KIF3B transports NR2A/APC complex and that its dysfunction is responsible for SCZ pathogenesis.

Authors+Show Affiliations

Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia. Unit of Neurological Disorders, Department of Genetic Medicine, Faculty of Medicine, Princess Al-Jawhara Center of Excellence in Research of Hereditary Disorders (PACER.HD), King Abdulaziz University, Jeddah, Saudi Arabia.Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Department of Anatomy and Neuroscience, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Center of Excellence in Genome Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31746486

Citation

Alsabban, Ashwaq Hassan, et al. "Kinesin Kif3b Mutation Reduces NMDAR Subunit NR2A Trafficking and Causes Schizophrenia-like Phenotypes in Mice." The EMBO Journal, vol. 39, no. 1, 2020, pp. e101090.
Alsabban AH, Morikawa M, Tanaka Y, et al. Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice. EMBO J. 2020;39(1):e101090.
Alsabban, A. H., Morikawa, M., Tanaka, Y., Takei, Y., & Hirokawa, N. (2020). Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice. The EMBO Journal, 39(1), pp. e101090. doi:10.15252/embj.2018101090.
Alsabban AH, et al. Kinesin Kif3b Mutation Reduces NMDAR Subunit NR2A Trafficking and Causes Schizophrenia-like Phenotypes in Mice. EMBO J. 2020 Jan 2;39(1):e101090. PubMed PMID: 31746486.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice. AU - Alsabban,Ashwaq Hassan, AU - Morikawa,Momo, AU - Tanaka,Yosuke, AU - Takei,Yosuke, AU - Hirokawa,Nobutaka, Y1 - 2019/11/20/ PY - 2018/11/06/received PY - 2019/10/19/revised PY - 2019/10/22/accepted PY - 2021/01/02/pmc-release PY - 2019/11/21/pubmed PY - 2019/11/21/medline PY - 2019/11/21/entrez KW - NMDAR KW - KIF3B KW - NR2A KW - neuronal plasticity KW - schizophrenia SP - e101090 EP - e101090 JF - The EMBO journal JO - EMBO J. VL - 39 IS - 1 N2 - The transport of N-methyl-d-aspartate receptors (NMDARs) is crucial for neuronal plasticity and synapse formation. Here, we show that KIF3B, a member of the kinesin superfamily proteins (KIFs), supports the transport of vesicles simultaneously containing NMDAR subunit 2A (NR2A) and the adenomatous polyposis coli (APC) complex. Kif3b+/- neurons exhibited a reduction in dendritic levels of both NR2A and NR2B due to the impaired transport of NR2A and increased degradation of NR2B. In Kif3b+/- hippocampal slices, electrophysiological NMDAR response was found decreased and synaptic plasticity was disrupted, which corresponded to a common feature of schizophrenia (SCZ). The histological features of Kif3b+/- mouse brain also mimicked SCZ features, and Kif3b+/- mice exhibited behavioral defects in prepulse inhibition (PPI), social interest, and cognitive flexibility. Indeed, a mutation of KIF3B was specifically identified in human SCZ patients, which was revealed to be functionally defective in a rescue experiment. Therefore, we propose that KIF3B transports NR2A/APC complex and that its dysfunction is responsible for SCZ pathogenesis. SN - 1460-2075 UR - https://www.unboundmedicine.com/medline/citation/31746486/Kinesin_Kif3b_mutation_reduces_NMDAR_subunit_NR2A_trafficking_and_causes_schizophrenia-like_phenotypes_in_mice L2 - https://doi.org/10.15252/embj.2018101090 DB - PRIME DP - Unbound Medicine ER -