Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo 113-0033, Japan.
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Hongo, Tokyo 113-0033, Japan; Laboratory for Molecular Psychiatry, RIKEN Center for Brain Science, Saitama 351-0198, Japan.
Cell Rep. 2021 Apr 13;35(2):108971. doi: 10.1016/j.celrep.2021.108971.
In schizophrenia (SCZ), neurons in the brain tend to undergo gross morphological changes, but the related molecular mechanism remains largely elusive. Using Kif3b mice as a model with SCZ-like behaviors, we found that a high-betaine diet can significantly alleviate schizophrenic traits related to neuronal morphogenesis and behaviors. According to a deficiency in the transport of collapsin response mediator protein 2 (CRMP2) by the KIF3 motor, we identified a significant reduction in lamellipodial dynamics in developing Kif3b neurons as a cause of neurite hyperbranching. Betaine administration significantly decreases CRMP2 carbonylation, which enhances the F-actin bundling needed for proper lamellipodial dynamics and microtubule exclusion and may thus functionally compensate for KIF3 deficiency. Because the KIF3 expression levels tend to be downregulated in the human prefrontal cortex of the postmortem brains of SCZ patients, this mechanism may partly participate in human SCZ pathogenesis, which we hypothesize could be alleviated by betaine administration.
在精神分裂症（SCZ）中，大脑中的神经元往往会发生明显的形态变化，但相关的分子机制在很大程度上仍难以捉摸。我们使用具有 SCZ 样行为的 Kif3b 小鼠作为模型，发现高甜菜碱饮食可以显著缓解与神经元形态发生和行为相关的精神分裂症特征。根据 KIF3 运动蛋白对 collapsin 反应介质蛋白 2（CRMP2）的转运缺陷，我们发现发育中的 Kif3b 神经元的片状伪足动力学显着减少，这是神经突过度分支的原因。甜菜碱的给药显著降低了 CRMP2 的碳化，这增强了适当的片状伪足动力学和微管排斥所必需的 F-肌动蛋白束，并可能因此在功能上补偿 KIF3 的缺乏。由于 KIF3 的表达水平在 SCZ 患者死后大脑的人类前额叶皮层中趋于下调，因此该机制可能部分参与人类 SCZ 的发病机制，我们假设甜菜碱给药可以缓解这种机制。
