Cooperation of synaptic adhesion molecules in synapse formation and function

突触粘附分子在突触形成和功能中的合作

• 批准号: 218389339
• 负责人: Professor Dr. Kurt Gottmann
• 金额: --
• 依托单位: Institut für Neuro- und Sinnesphysiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/218389339?language=en
• 关键词: Cooperation; synaptic; adhesion; molecules; synapse

Synaptic cell adhesion molecules (SCAMs) mediate transsynaptic signaling by protein-protein interactions across the synaptic cleft. SCAM signaling is thought to control synapse formation and maturation, and to be involved in neurological diseases. Several diverse types of SCAMs have been characterized at the molecular level. However, how they cooperate with each other to achieve the precise regulation of synapse formation and function is largely unknown. We will mainly focus on the cooperation of N-cadherin and Neuroligin-1 that has recently been found by our group (Stan et al., 2010). We will analyse this cooperation at nascent synapses to molecularly understand its role in synaptic vesicle accumulation. Neuroligin-1 function will be studied in conditional N-cadherin knockout neurons, and upon RNA interference-mediated knockdown of catenins and postsynaptic scaffolding proteins. In addition, a potential crossregulatory role of signaling cascades, e.g. Wnt signaling will be addressed. To learn how NMDA receptors are modulating SCAM activity, we will study the influence of NMDA receptor activity on the N-cadherin Neuroligin-1 cooperation. To further address whether cooperation mechanisms are of general importance for SCAM function, we will investigate whether other SCAMs (SynCAMs; LRRTMs) also require a cooperation with N-cadherin. In addition to nascent synapses, we will study the cooperation of N-cadherin and Neuroligin-1 at fully functional, mature glutamatergic synapses. We will use an electrophysiological approach to analyse the molecular mechanisms (involvement of N-cadherin) underlying the modulation of presynaptic release probability by Neuroligin-1.

突触细胞粘附分子（SCAMs）通过跨突触间隙的蛋白质-蛋白质相互作用介导跨突触信号传导。SCAM信号被认为控制突触的形成和成熟，并参与神经系统疾病。几种不同类型的SCAMs已在分子水平上进行了表征。然而，它们如何相互合作以实现突触形成和功能的精确调节在很大程度上是未知的。我们将主要关注我们小组最近发现的N-钙粘蛋白和神经连接蛋白-1的合作（Stan et al.，2010年）。我们将在新生突触中分析这种合作，以从分子上了解其在突触囊泡积累中的作用。神经连接素-1的功能将在条件性N-钙粘蛋白敲除神经元中进行研究，并在RNA干扰介导的连环蛋白和突触后支架蛋白敲除后进行研究。此外，一个潜在的交叉调节作用的信号级联，如Wnt信号将得到解决。为了了解NMDA受体如何调节SCAM活性，我们将研究NMDA受体活性对N-钙粘蛋白Neuroligin-1合作的影响。为了进一步解决合作机制是否对SCAM功能具有普遍重要性，我们将调查其他SCAMs（SynCAM; LRRTMs）是否也需要与N-cadherin合作。除了新生的突触，我们将研究的合作N-钙粘蛋白和Neuroligin-1在功能齐全，成熟的突触。我们将使用电生理学方法来分析神经连接素-1调制突触前释放概率的分子机制（N-钙粘蛋白的参与）。