Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice.,The EMBO Journal

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Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice.
The EMBO Journal ( IF 9.4 ) Pub Date : 2019-11-20 , DOI: 10.15252/embj.2018101090
Ashwaq Hassan Alsabban _{1,

2,

3} , Momo Morikawa ₁ , Yosuke Tanaka ₁ , Yosuke Takei _{1,

4} , Nobutaka Hirokawa _{1,

5}

Affiliation

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.

中文翻译：

驱动蛋白 Kif3b 突变会减少 NMDAR 亚基 NR2A 的运输并导致小鼠出现精神分裂症样表型。

N-甲基-d-天冬氨酸受体 (NMDAR) 的运输对于神经元可塑性和突触形成至关重要。在这里，我们发现 KIF3B 是驱动蛋白超家族蛋白 (KIF) 的成员，支持同时含有 NMDAR 亚基 2A (NR2A) 和腺瘤性息肉病大肠杆菌 (APC) 复合物的囊泡的运输。由于 NR2A 运输受损和 NR2B 降解增加，Kif3b+/- 神经元表现出 NR2A 和 NR2B 树突水平降低。在 Kif3b+/- 海马切片中，发现电生理 NMDAR 反应下降，突触可塑性被破坏，这对应于精神分裂症 (SCZ) 的一个共同特征。 Kif3b+/-小鼠大脑的组织学特征也模仿了SCZ特征，并且Kif3b+/-小鼠在前脉冲抑制（PPI）、社交兴趣和认知灵活性方面表现出行为缺陷。事实上，在人类 SCZ 患者中特别发现了 KIF3B 突变，在救援实验中发现该突变存在功能缺陷。因此，我们认为 KIF3B 转运 NR2A/APC 复合物，其功能障碍是 SCZ 发病机制的原因。

更新日期：2020-01-02

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