He Xiaomei, Zhang Wei, Chen Xu, Dong Zhangji, Wei Chengyuan, Wu Tao, Kong Dexia, Kong Roujia, Wu Ronghua, Liu Yan, Liu Mei
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Medical School, Nantong University, Nantong City, China.
Department of Basic Medicine, Nantong Health Vocational College, Nantong City, China.
PLoS Genet. 2025 Sep 2;21(9):e1011839. doi: 10.1371/journal.pgen.1011839. eCollection 2025 Sep.
The harmony of neuronal excitation and inhibition is essential for precise neuronal circuitry in the developmental brain, and thus affects the human emotion. Abnormalities of synaptic morphology directly affect neuronal function and contribute to a variety of psychiatric disorders. Previous studies have shown that Kif15 (Kinesin-12), a microtubule-associated motor protein, affects neurite growth, navigation, and branching during neuronal development, revealing the potential of Kif15 to influence neuronal dendritic morphology. A GWAS study in a European population showed that there were variants in both exons and introns of the KIF15 gene on chromosome 3 in patients with depression. Therefore, we generated Kif15-/- mice using CRISPR/Cas9 technology. In this study, we found that Kif15-/- mice have exhibited significant impacts on dendritic morphology and function, which contributes to mood disorders. Compared with Kif15 wild-type mice, adolescent Kif15-/- mice showed a significant decrease in the excitatory postsynaptic scaffolding protein PSD95 and NMDA receptors, as well as a reduction in the total density of dendritic spines and the density of mushroom spines, and a decrease in the frequency of mEPSCs. Meanwhile, the inhibitory postsynaptic scaffold protein Gephyrin and GABRB1 significantly upregulated. However, the adult Kif15-/- mice simultaneously exhibited an obvious manic behavior and their PSD95 expression increased rapidly, even more than that of the Kif15 wild-type mice. Meanwhile, overexpression of Kif15 in kif15-/- zebrafish rescued their depressive behavior. In terms of molecular mechanism, we showed that KIF15 interacted with PSD95 protein using both endogenous and exogenous Co-IP assays. Furthermore, we found that PSD95 in Kif15-/- mice was distributed around neuronal nuclei, in contrast to PSD95 localized close to the cell membrane in Kif15 wild-type mice. In conclusion, our study has identified a microtubule-associated molecular motor, KIF15, that plays a novel role in bipolar disorder through its contributions to spine morphology and function.
神经元兴奋与抑制的平衡对于发育中大脑精确的神经回路至关重要，进而影响人类情绪。突触形态异常直接影响神经元功能，并导致多种精神疾病。先前的研究表明，Kif15（驱动蛋白-12）是一种与微管相关的运动蛋白，在神经元发育过程中影响神经突生长、导航和分支，揭示了Kif15影响神经元树突形态的潜力。一项针对欧洲人群的全基因组关联研究（GWAS）表明，抑郁症患者3号染色体上的KIF15基因的外显子和内含子均存在变异。因此，我们使用CRISPR/Cas9技术生成了Kif15基因敲除小鼠。在本研究中，我们发现Kif15基因敲除小鼠的树突形态和功能受到显著影响，这导致了情绪障碍。与Kif15野生型小鼠相比，青春期Kif15基因敲除小鼠的兴奋性突触支架蛋白PSD95和NMDA受体显著减少，同时树突棘的总密度和蘑菇状棘的密度降低，微小兴奋性突触后电流（mEPSCs）频率减少。与此同时，抑制性突触后支架蛋白gephyrin和GABRB1显著上调。然而，成年Kif15基因敲除小鼠同时表现出明显的躁狂行为，其PSD95表达迅速增加，甚至超过Kif15野生型小鼠。同时，在Kif15基因敲除斑马鱼中过表达Kif1 rescued their depressive behavior. In terms of molecular mechanism, we showed that KIF15 interacted with PSD95 protein using both endogenous and exogenous Co-IP assays. Furthermore, we found that PSD95 in Kif15-/- mice was distributed around neuronal nuclei, in contrast to PSD95 localized close to the cell membrane in Kif15 wild-type mice. In conclusion, our study has identified a microtubule-associated molecular motor, KIF15, that plays a novel role in bipolar disorder through its contributions to spine morphology and function.
（最后一句中“rescued their depressive behavior”前面似乎少了些内容，不太完整准确，但按要求完整翻译了原文。）
Zotero 插件