The role of neuroligin-3 and neuroligin-4 in synaptic transmission, long-term synaptic plasticity and excitation/inhibition balance in dentate granule cells

Neuroligin-3和neuroligin-4在齿状颗粒细胞突触传递、长期突触可塑性和兴奋/抑制平衡中的作用

• 批准号: 315380608
• 负责人: Professor Dr. Peter Jedlicka
• 金额: --
• 依托单位: Institut für Medizinische Informatik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/315380608?language=en
• 关键词: role; neuroligin; synaptic; transmission; long

The dentate gyrus of the hippocampus is important for learning and memory. Efficient processing of information in the dentate network requires a fine balance of excitation and inhibition. This balance is controlled by molecular players at excitatory and inhibitory synapses. Therefore, in this project proposal, we focus on neuroligins (NLs). Neuroligins form a group of synaptic proteins, which play a critical role in balancing excitation and inhibition, as has been shown by our previous work on NL1 and NL2. NL3 and NL4 are clinically the most important neuroligins since gene mutations in NL3 and NL4 have been associated with autism spectrum disorders. Dysbalance between excitation and inhibition is thought to be the central mechanism underlying the pathogenesis of autism. However the regulation of the excitation-inhibition balance by NL3 and NL4 is poorly understood. Therefore, in this project proposal we focus on NL3- and NL4-dependent mechanisms for fine-tuning of excitatory and inhibitory synaptic transmission. Our main questions are: How do NL3 and NL4 influence the functional properties of dentate granule cells and their major excitatory input synapses? Does the loss of NL3 or NL4 in granule cells lead to impairments of their excitability or synaptic input properties and synaptic plasticity? How do NL3 and NL4 influence the in vivo network activity in the dentate gyrus circuitry? What are the effects of NL3 or NL4 deletion on network inhibition? What are the effects of altered NL3 or NL4 expression on excitation/inhibition balance selectively in dentate granule cells? Do NL3 or NL4 participate in maintaining normal output of dentate granule cells?This project pursues a novel experimental approach to uncover the role of NL3 and NL4 in the dentate gyrus of live animals. Specifically, the project proposes to use electrophysiological recordings in combination with neurohistological methods to unravel, at a cellular and network level, the functional impact of NL3 and NL4 loss in granule cells of the dentate gyrus. We will use conditional, cell-type specific knockout of NL3 to investigate the effects of selective deletion of NL3 in dentate granule cells. We aim to study the role of NL3 and NL4 in the dentate gyrus (1) in vivo, by using extracellular field potential recordings in the intact dentate gyrus circuitry of live animals, (2) ex vivo and in vitro, by using intracellular patch-clamp recordings and performing immunohistological analyses. The combination of genetic, functional and morphological methods will allow us to test the hypotheses concerning NL3 and NL4 effects on the balance of inhibition and excitation within the dentate gyrus.

海马齿状回对学习和记忆很重要。在齿状网络中有效地处理信息需要在兴奋和抑制之间取得良好的平衡。这种平衡是由兴奋性和抑制性突触的分子参与者控制的。因此，在本项目提案中，我们重点介绍神经连接蛋白(NLS)。神经连接蛋白形成一组突触蛋白，在平衡兴奋和抑制方面发挥关键作用，我们之前对NL1和NL2的研究表明。NL3和NL4是临床上最重要的神经连接蛋白，因为NL3和NL4的基因突变与自闭症谱系障碍有关。兴奋和抑制之间的失衡被认为是自闭症发病的中心机制。然而，NL3和NL4对兴奋-抑制平衡的调节知之甚少。因此，在这个项目提案中，我们将重点放在NL3和NL4依赖的机制上，以微调兴奋性和抑制性突触传递。我们的主要问题是：NL3和NL4如何影响齿状颗粒细胞及其主要兴奋性输入突触的功能特性？颗粒细胞中NL3或NL4的缺失是否会导致它们的兴奋性或突触输入特性和突触可塑性受损？NL3和NL4如何影响齿状回回路的活体网络活动？NL3或NL4缺失对网络抑制有何影响？在齿状颗粒细胞中，NL3或NL4表达的改变对选择性兴奋/抑制平衡有什么影响？NL3或NL4参与维持齿状颗粒细胞的正常输出吗？本项目寻求一种新的实验方法来揭示NL3和NL4在活体动物齿状回中的作用。具体地说，该项目建议使用电生理记录结合神经组织学方法在细胞和网络水平上揭示NL3和NL4丢失对齿状回颗粒细胞的功能影响。我们将使用条件性、细胞类型特异性的NL3基因敲除来研究选择性缺失NL3在齿状颗粒细胞中的作用。我们的目标是研究NL3和NL4在齿状回中的作用：(1)在活体动物的完整齿状回回路中，通过细胞外场电位记录；(2)通过细胞内膜片钳记录和免疫组织学分析，在体外和体外研究NL3和NL4在齿状回中的作用。基因、功能和形态方法的结合将使我们能够检验关于NL3和NL4对齿状回内抑制和兴奋平衡的影响的假说。

项目成果

Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1

小鼠脑蛋白质组学将 MDGA1 和 CACHD1 确定为阿尔茨海默病蛋白酶 BACE1 的体内底物

• DOI: 10.1096/fj.201902347r
• 发表时间: 2020
• 期刊: The FASEB Journal
• 作者: Rudan Njavro J;Jedlicka P;Müller SA;Lichtenthaler SF
• 通讯作者: Lichtenthaler SF

Structural homo- and heterosynaptic plasticity in mature and adult newborn rat hippocampal granule cells

• DOI: 10.1073/pnas.1801889115
• 发表时间: 2018-05-15
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Jungenitza, Tassilo;Beining, Marcel;Schwarzacher, Stephan W.
• 通讯作者: Schwarzacher, Stephan W.