biostudies-literatureAlsabban AHPrincess Al-Jawhara Center of Excellence in Research of Hereditary Disorders (PACER.HD)King Abdulaziz University (KAU)MEXT | Japan Society for the Promotion of Science (JSPS)Ministry of Higher Education of the Kingdom of Saudi Arabia (MOHE)Strategic Research Program for Brain Science (SRPBS)Japan Agency for Medical Research and Development (AMED)e101090https://www.ebi.ac.uk/biostudies/studies/S-EPMC6939202biostudies-literatureUnknown39(1)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.The EMBO journalKinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice.PMC6939202JP23000013JP18dm0207047JP16H06372JP18dm0107084h0002Alsabban AHTanaka YMorikawa MHirokawa NTakei YfalseKinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice.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.2020-01-01T00:00:00Z2020 Jan2021-02-20T18:01:44Z2021-02-20T18:01:44ZS-EPMC69392023174648610.15252/embj.2018101090