Department of Developmental Neurobiology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
J Physiol. 2012 Feb 15;590(4):777-92. doi: 10.1113/jphysiol.2011.220236. Epub 2011 Dec 6.
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.
肿瘤抑制因子 PTEN 是磷脂酰肌醇 3-激酶 (PI3K) 信号通路的核心负调节剂，该通路介导各种组织中的多种过程。在神经系统中，PI3K 通路调节增殖、迁移、细胞大小、突触传递和可塑性。在人类中，自闭症、癫痫和共济失调等神经异常与遗传性 PTEN 突变有关。在啮齿动物中，早期发育过程中 Pten 的缺失与神经元迁移广泛缺陷以及神经元和突触密度显著肥大有关；然而，其对突触传递和可塑性的影响是直接的还是通过结构异常介导的仍然未知。在这里，我们分析了 Pten 条件性敲除小鼠中的神经元和突触结构和功能，其中该基因在出生后从兴奋性神经元中缺失。使用双光子成像、高尔基染色、免疫组织化学、电子显微镜和电生理工具，我们确定 Pten 的缺失不会影响海马体发育、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，都出现缺陷。这些缺陷与空间记忆受损相吻合，这是在水迷宫任务中测量的。PI3K 通路的正向下游调节因子 Pdk1 的缺失挽救了 Pten 介导的突触可塑性缺陷，但没有挽救空间记忆缺陷。这些结果表明，PTEN 独立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。
