Phosphatase and tensin homologue (PTEN) regulates synaptic plasticity independently of its effect on neuronal morphology and migration
Phosphatase and tensin homologue (PTEN) regulates synaptic plasticity independently of its effect on neuronal morphology and migration
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DOI：
10.1113/jphysiol.2011.220236
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发表时间：
2012-02-01
影响因子：
5.5
通讯作者：
Zakharenko, Stanislav S.
中科院分区：
文献类型：
--
作者：
Sperow, Margaret;Berry, Raymond B.;Zakharenko, Stanislav S.
肿瘤抑制因子PTEN是磷脂酰肌醇3-激酶（PI 3 K）信号通路的中心负调节因子，其介导各种组织中的不同过程。在神经系统中，PI 3 K通路调节增殖、迁移、细胞大小、突触传递和可塑性。在人类中，神经系统异常，如自闭症，癫痫发作和共济失调与遗传性PTEN突变有关。在啮齿类动物中，Pten在早期发育过程中的损失与神经元迁移的广泛缺陷和神经元和突触密度的大量肥大有关;然而，其对突触传递和可塑性的影响是直接的还是由结构异常介导的仍然未知。在这里，我们分析了神经元和突触的结构和功能的Pten条件性基因敲除小鼠中的基因被删除的兴奋性神经元出生后。使用双光子成像，高尔基体染色，免疫组织化学，电子显微镜，和电生理工具，我们确定，Pten损失不影响海马发育，神经元或突触结构，或基础兴奋性突触传递。然而，它确实会导致兴奋性突触传递的两种主要形式的突触可塑性（长时程增强和长时程抑制）的缺陷。这些缺陷与水迷宫任务中测量的空间记忆受损相吻合。Pdk 1编码PI 3 K通路的正下游调节因子，Pdk 1的缺失挽救了Pten介导的突触可塑性缺陷，但在空间记忆中没有。这些结果表明，PTEN独立地调节海马神经元的功能和结构特性，并直接参与突触可塑性的机制。
The tumour suppressor PTEN is the central negative regulator of the phosphatidylinositol 3-kinase (PI3K) signalling pathway, which mediates diverse processes in various tissues. In the nervous system, the PI3K pathway modulates proliferation, migration, cellular size, synaptic transmission and plasticity. In humans, neurological abnormalities such as autism, seizures and ataxia are associated with inherited PTEN mutations. In rodents, Pten loss during early development is associated with extensive deficits in neuronal migration and substantial hypertrophy of neurons and synaptic densities; however, whether its effect on synaptic transmission and plasticity is direct or mediated by structural abnormalities remains unknown. Here we analysed neuronal and synaptic structures and function in Pten-conditional knockout mice in which the gene was deleted from excitatory neurons postnatally. Using two-photon imaging, Golgi staining, immunohistochemistry, electron microscopy, and electrophysiological tools, we determined that Pten loss does not affect hippocampus development, neuronal or synaptic structures, or basal excitatory synaptic transmission. However, it does cause deficits in both major forms of synaptic plasticity, long-term potentiation and long-term depression, of excitatory synaptic transmission. These deficits coincided with impaired spatial memory, as measured in water maze tasks. Deletion of Pdk1, which encodes a positive downstream regulator of the PI3K pathway, rescued Pten-mediated deficits in synaptic plasticity but not in spatial memory. These results suggest that PTEN independently modulates functional and structural properties of hippocampal neurons and is directly involved in mechanisms of synaptic plasticity.