Effects of synaptic adhesion molecules on the survival of adult born granule cells in the dentate gyrus

突触粘附分子对齿状回成体出生颗粒细胞存活的影响

• 批准号: 240088636
• 负责人: Professor Dr. Valentin Stein
• 金额: --
• 依托单位: Institut für Physiologie II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/240088636?language=en
• 关键词: Effects; synaptic; adhesion; molecules; survival

Neurons are born even in adult mammals and provide an additional level of plasticity to the existing neuronal circuitry. The functional integration of these newborn neurons determines the impact of this form of plasticity. Many newborn neurons do not survive the first weeks and only a fraction is fully integrated into the existing neuronal network. The process of network integration and survival is intimately linked to the formation of glutamatergic synapses. Synaptic adhesion molecules have been shown to tightly regulate the formation of synapses. Surprisingly, this class of molecules has not been studied in the context of synapse formation of newborn neurons. We recently demonstrated that the synaptic adhesion molecule SynCAM1 regulates the number of synapses. Confocal microscopy of the dentate gyrus of animals with GFP labeled neurons revealed that the number of GFP expressing neurons is nearly doubled in SynCAM1 overexpressing animals, while SynCAM1 knockout animals showed a strong reduction in the number of GFP positive neurons. Here, we hypothesize that the synaptogenic function of SynCAM1 helps newborn neurons to form excitatory synapses leading to a more reliable functional integration into the existing network and thereby increasing the chance to survive. Using SynCAM1 knockout and overexpressing animals we will now test this hypothesis by determining the number of surviving neurons compared to newly generated neurons. In a second step we plan to compare the morphology and synaptic function of these neurons at different time points to study the time course of the development. Finally, we want to address the question at which time point during maturation of newborn neurons the aided synapse formation is required. This project will increase our understanding of the mechanisms underlying the integration of newborn neurons into the existing neuronal network. In addition it might be of interest for future therapeutic approaches that rely on the replacement of neurons, especially in diseases like Alzheimer or Parkinson.

神经元甚至在成年哺乳动物中诞生，并为现有的神经元回路提供额外的可塑性。这些新生神经元的功能整合决定了这种形式的可塑性的影响。许多新生神经元在最初几周内无法存活，只有一小部分完全整合到现有的神经元网络中。网络整合和存活的过程与突触的形成密切相关。突触粘附分子已被证明紧密调节突触的形成。令人惊讶的是，这类分子尚未在新生神经元突触形成的背景下进行研究。我们最近证明突触粘附分子SynCAM 1调节突触的数量。用GFP标记神经元的动物的齿状回的共聚焦显微镜显示，在SynCAM 1过表达的动物中，GFP表达神经元的数量几乎加倍，而SynCAM 1敲除的动物显示GFP阳性神经元的数量大幅减少。在这里，我们假设SynCAM 1的突触发生功能有助于新生神经元形成兴奋性突触，从而更可靠地整合到现有的网络中，从而增加生存的机会。使用SynCAM 1敲除和过表达的动物，我们现在将通过确定与新生成的神经元相比存活神经元的数量来测试这一假设。在第二步中，我们计划比较这些神经元在不同时间点的形态和突触功能，以研究发育的时间过程。最后，我们要解决的问题是，在新生神经元成熟过程中的哪个时间点需要辅助突触的形成。该项目将增加我们对新生神经元整合到现有神经元网络中的机制的理解。此外，它可能对未来依赖于神经元替代的治疗方法感兴趣，特别是在阿尔茨海默病或帕金森病等疾病中。