Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice
Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice
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DOI：
10.15252/embj.2018101090
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发表时间：
2019-11-20
期刊：
影响因子：
11.4
通讯作者：
Hirokawa, Nobutaka
中科院分区：
文献类型：
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作者：
Alsabban, Ashwaq Hassan;Morikawa, Momo;Hirokawa, Nobutaka
N-甲基-d-天冬氨酸受体（NMDARs）的转运对神经元的可塑性和突触形成至关重要。在这里，我们表明，KIF 3B，驱动蛋白超家族蛋白（KIFs）的成员，支持运输囊泡同时含有NMDAR亚基2A（NR 2A）和腺瘤性息肉病大肠杆菌（APC）复合物。Kif 3b（+/-）神经元由于NR 2A的转运受损和NR 2B的降解增加而表现出NR 2A和NR 2B的树突水平的降低。在Kif 3b（+/-）海马脑片中，发现电生理NMDAR反应降低，突触可塑性被破坏，这对应于精神分裂症（SCZ）的共同特征。Kif 3b（+/-）小鼠脑的组织学特征也模仿SCZ特征，并且Kif 3b（+/-）小鼠在前脉冲抑制（PPI）、社会兴趣和认知灵活性方面表现出行为缺陷。事实上，在人类SCZ患者中特异性地鉴定了KIF 3B的突变，其在拯救实验中被揭示为功能缺陷。因此，我们提出KIF 3B转运NR 2A/APC复合物，其功能障碍是SCZ发病机制的原因。
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.