Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities
Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities
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DOI：
10.1016/j.neuroscience.2007.10.048
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发表时间：
2008-01-24
期刊：
影响因子：
3.3
通讯作者：
Baker, S. J.
中科院分区：
文献类型：
--
作者：
Fraser, M. M.;Bayazitov, I. T.;Baker, S. J.
磷脂酰肌醇3-激酶(PI3K)信号通路调节多种组织类型的生长、增殖和细胞存活，在神经系统中发挥特殊的作用，包括影响神经元的极性、树突的分支和突触的可塑性。肿瘤抑制蛋白紧张素同源磷酸酶(PTEN)是PI3K途径的中心负调控因子。生殖系PTEN突变导致许多组织中的癌症易感性、巨头症和良性错构瘤，包括Lhermitte-Duclos病，一种小脑生长障碍。已观察到包括自闭症、癫痫发作和共济失调在内的神经异常与遗传性PTEN突变具有可变外显性相关。目前尚不清楚PTEN活性丧失如何导致神经功能障碍。为了探讨Pten缺陷对神经元结构和功能的影响，我们分析了Pten条件性基因敲除小鼠Pten缺陷神经元的几个超微结构特征。用高尔基染色显示完整的神经元形态，我们观察到Pten缺陷神经元的核和胞体的大小增加伴随着神经元投射口径的增大和树突棘密度的增加。电子显微镜检查显示大脑皮层和小脑异常突触结构增大。严重的髓鞘缺陷包括围绕着肥大轴突的骨髓鞘增厚和解体。在小脑观察到正常口径的轴突髓鞘形成缺陷，提示Pten缺陷的少突胶质细胞存在内在异常。我们没有在野生型或条件性Pten杂合子小鼠中观察到这些异常。此外，条件性缺失Pten显著削弱了突触传递和兴奋性突触上CA3和CA1锥体神经元之间的突触可塑性。这些数据表明，Pten参与了控制神经元和突触结构的发育以及随后的突触功能的机制。(C)2008年IBRO。爱思唯尔有限公司出版。保留所有权利。
The phosphatidylinositol 3-kinase (PI3K) signaling pathway modulates growth, proliferation and cell survival in diverse tissue types and plays specialized roles in the nervous system including influences on neuronal polarity, dendritic branching and synaptic plasticity. The tumor-suppressor phosphatase with tensin homology (PTEN) is the central negative regulator of the PI3K pathway. Germline PTEN mutations result in cancer predisposition, macrocephaly and benign hamartomas in many tissues, including Lhermitte-Duclos disease, a cerebellar growth disorder. Neurological abnormalities including autism, seizures and ataxia have been observed in association with inherited PTEN mutation with variable penetrance. It remains unclear how loss of PTEN activity contributes to neurological dysfunction. To explore the effects of Pten deficiency on neuronal structure and function, we analyzed several ultra-structural features of Pten-deficient neurons in Pten conditional knockout mice. Using Golgi stain to visualize full neuronal morphology, we observed that increased size of nuclei and somata in Pten-deficient neurons was accompanied by enlarged caliber of neuronal projections and increased dendritic spine density. Electron microscopic evaluation revealed enlarged abnormal synaptic structures in the cerebral cortex and cerebellum. Severe myelination defects included thickening and unraveling of the myelin sheath surrounding hypertrophic axons in the corpus callosum. Defects in myelination of axons of normal caliber were observed in the cerebellum, suggesting intrinsic abnormalities in Pten-deficient oligodendrocytes. We did not observe these abnormalities in wild-type or conditional Pten heterozygous mice. Moreover, conditional deletion of Pten drastically weakened synaptic transmission and synaptic plasticity at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. These data suggest that Pten is involved in mechanisms that control development of neuronal and synaptic structures and subsequently synaptic function. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.