Fraser M M, Bayazitov I T, Zakharenko S S, Baker S J
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
Neuroscience. 2008 Jan 24;151(2):476-88. doi: 10.1016/j.neuroscience.2007.10.048. Epub 2007 Nov 17.
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.
磷脂酰肌醇3激酶（PI3K）信号通路调节多种组织类型中的生长、增殖和细胞存活，并在神经系统中发挥特殊作用，包括影响神经元极性、树突分支和突触可塑性。具有张力蛋白同源性的肿瘤抑制磷酸酶（PTEN）是PI3K通路的主要负调节因子。种系PTEN突变会导致癌症易感性、巨头畸形以及许多组织中的良性错构瘤，包括小脑生长障碍Lhermitte-Duclos病。与具有可变外显率的遗传性PTEN突变相关的神经学异常包括自闭症、癫痫和共济失调。目前尚不清楚PTEN活性丧失如何导致神经功能障碍。为了探究Pten缺陷对神经元结构和功能的影响，我们分析了Pten条件性敲除小鼠中Pten缺陷神经元的几个超微结构特征。使用高尔基染色来观察完整的神经元形态，我们观察到Pten缺陷神经元的细胞核和胞体大小增加，同时神经元突起的口径增大，树突棘密度增加。电子显微镜评估显示大脑皮层和小脑中存在扩大的异常突触结构。严重的髓鞘形成缺陷包括胼胝体中围绕肥大轴突的髓鞘增厚和解开。在小脑中观察到正常口径轴突的髓鞘形成缺陷，提示Pten缺陷的少突胶质细胞存在内在异常。我们在野生型或条件性Pten杂合小鼠中未观察到这些异常。此外，Pten的条件性缺失极大地削弱了海马体中CA3和CA1锥体神经元之间兴奋性突触处的突触传递和突触可塑性。这些数据表明，Pten参与了控制神经元和突触结构发育以及随后突触功能的机制。
