P-Rex1 Overexpression Results in Aberrant Neuronal Polarity and Psychosis-Related Behaviors
P-Rex1 Overexpression Results in Aberrant Neuronal Polarity and Psychosis-Related Behaviors
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P-Rex1 过度表达导致神经元极性异常和精神病相关行为
DOI：
10.1007/s12264-019-00408-2
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发表时间：
2019-12-01
影响因子：
5.6
通讯作者：
Li, Jun
中科院分区：
文献类型：
--
作者：
Li, Qiongwei;Wang, Lifang;Li, Jun
神经元极性参与多个发育阶段，包括皮质神经元迁移、多极到双极转变、轴突起始、顶端/基底树突分化和棘形成。所有这些过程都与细胞骨架有关，并通过精确的时间和控制基因表达来调节。例如，已知P-Rex 1（磷脂酰肌醇-3，4，5-三磷酸依赖性Rac交换因子1）基因对于细胞骨架重组、细胞运动性和迁移是重要的。P-Rex 1蛋白的缺乏导致异常的神经元迁移和突触可塑性，以及自闭症相关的行为。尽管如此，P-Rex 1过表达对神经元发育和高级脑功能的影响仍不清楚。在本研究中，我们探讨了P-Rex 1过表达对小鼠大脑发育和精神病相关行为的影响。在胚胎第14.5天的子宫内电穿孔用于评估P-Rex 1过表达对细胞极性和迁移的影响。采用原代神经元培养方法，观察P-Rex 1过表达对神经元突起形成和棘形态的影响。此外，P-Rex 1在小鼠内侧前额叶皮质（mPFC）中的过表达被用于评估精神病相关行为。我们发现，P-Rex 1过度表达导致异常极性，抑制多极到双极的转换，导致异常的神经元迁移。此外，P-Rex 1过表达影响了神经元的早期发育，表现为神经突起起始异常，细胞骨架改变，轴突长度和树突复杂性降低，并导致原代培养神经元出现过多的板状伪足。此外，P-Rex 1过表达降低了棘的密度，增加了高度，宽度和头部面积在体外和体内。行为测试表明，P-Rex 1在小鼠mPFC过表达引起焦虑样行为和感觉运动门控缺陷。适当的P-Rex 1水平在大脑皮层发育中起着至关重要的作用，过量的P-Rex 1可能与精神病相关行为有关。
Neuronal polarity is involved in multiple developmental stages, including cortical neuron migration, multipolar-to-bipolar transition, axon initiation, apical/basal dendrite differentiation, and spine formation. All of these processes are associated with the cytoskeleton and are regulated by precise timing and by controlling gene expression. The P-Rex1 (phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 1) gene for example, is known to be important for cytoskeletal reorganization, cell motility, and migration. Deficiency of P-Rex1 protein leads to abnormal neuronal migration and synaptic plasticity, as well as autism-related behaviors. Nonetheless, the effects of P-Rex1 overexpression on neuronal development and higher brain functions remain unclear. In the present study, we explored the effect of P-Rex1 overexpression on cerebral development and psychosis-related behaviors in mice. In utero electroporation at embryonic day 14.5 was used to assess the influence of P-Rex1 overexpression on cell polarity and migration. Primary neuron culture was used to explore the effects of P-Rex1 overexpression on neuritogenesis and spine morphology. In addition, P-Rex1 overexpression in the medial prefrontal cortex (mPFC) of mice was used to assess psychosis-related behaviors. We found that P-Rex1 overexpression led to aberrant polarity and inhibited the multipolar-to-bipolar transition, leading to abnormal neuronal migration. In addition, P-Rex1 overexpression affected the early development of neurons, manifested as abnormal neurite initiation with cytoskeleton change, reduced the axon length and dendritic complexity, and caused excessive lamellipodia in primary neuronal culture. Moreover, P-Rex1 overexpression decreased the density of spines with increased height, width, and head area in vitro and in vivo. Behavioral tests showed that P-Rex1 overexpression in the mouse mPFC caused anxiety-like behaviors and a sensorimotor gating deficit. The appropriate P-Rex1 level plays a critical role in the developing cerebral cortex and excessive P-Rex1 might be related to psychosis-related behaviors.