Molecular mechanisms of target-specific synapse formation

项目摘要/摘要 正常的大脑功能要求神经元与特定类型的靶神经元形成特定类型的突触。 突触特异性过程中的缺陷可以改变大脑活动，并可能是许多类型精神疾病的基础 疾病，但我们对突触专一性形成的机制知之甚少。我们最近发现 细胞黏附分子Kirrel3被选择性地要求形成一种特定类型的突触 海马区DG神经元与GABA神经元之间的相互作用。这种突触为CA3和CA3提供前馈抑制 Kirrel3基因缺失的小鼠CA3神经元活性显著增加。这确立了Kirrel3在功能上的地位 相关的靶向特异性突触分子，但目前仍不清楚Kirrel3的作用机制。 通过一系列体外测试，我们的新的初步数据表明，Kirrel3与其他Kirrel3分子结合 在顺式和反式中，它指导突触前和突触后的组装，其功能尚未确定。 神经元分子。在这里，我们将检验中心假设，同性恋，跨细胞的Kirrel3相互作用 通过将突触蛋白招募到轴突-树突接触点，在体内使DG到GABA的突触成核。在目标1中， 我们将准确地确定在哪里、何时以及需要多少Kirrel3来构建海马DG-to-GABA 体内的突触。在目标2中，我们将通过定义控制Kirrel3信号的属性来确定Kirrel3信号机制 Kirrel3亚型的亚细胞定位及Kirrel3相互作用蛋白的鉴定团结在一起， Kirrel3基因的研究为识别靶向特异性突触的机制提供了新的途径 形成和理解突触特异性变化如何影响海马环路的框架 功能，它在学习和记忆过程中起着核心作用。

PROJECT SUMMARY/ABSTRACT Proper brain function requires that neurons make specific types of synapses with specific types of target neurons. Defects in this process of synapse specficity can alter brain activity and may underlie many types of mental illnesses but we know little about the mechanisms by which synapse specificity develops. We recently discovered that the cell adhesion molecule Kirrel3 is selectively required to form a specific type of synapse that connects DG neurons to GABA neurons in the hippocampus. This synapse provides feed-forward inhibition to CA3 and Kirrel3 null mice have significantly elevated CA3 neuron activity. This established Kirrel3 as a functionally relevant target-specific synaptogenic molecule but we still do not know the mechanism of Kirrel3 function. Through a series of in vitro assays, our new preliminary data suggests that Kirrel3 binds other Kirrel3 molecules in cis and trans, directs the assembly of pre- and post-synapses, and its function requires yet to be identified neuronal molecules. Here, we will test the central hypothesis that homophilic, trans-cellular Kirrel3 interactions nucleate DG-to-GABA synapses in vivo by recruiting synaptic proteins to axon-dendrite contact points. In Aim 1, we will determine precisely where, when, and how much Kirrel3 is required to build hippocampal DG-to-GABA synapses in vivo. In Aim 2, we will identify Kirrel3 signaling mechanisms by defining properties controlling the differential subcellular localization of Kirrel3 isoforms and identifing Kirrel3 interacting proteins. Together, the study of Kirrel3 provides a new approach to identify the still elusive mechanisms of target-specific synapse formation and a framework for understanding how changes in synapse specificity impact hippocampal circuit function, which plays a central role in learning and memory processes.