The intellectual disability-associated gene kirrel3 in synapse development

突触发育中智力障碍相关基因 kirrel3

• 批准号: 9095917
• 负责人: Megan Elise Williams
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095917
• 关键词: Area; Attenuated; Autistic Disorder; Axon; Behavioral; Binding; Biological Assay; Brain; Cells; Cognition Disorders; Complex; Copy Number Polymorphism; Defect; Dendrites; Development; Disease; Electron Microscopy; Filopodia; Functional disorder; Genes; Head; Health; Hippocampal Mossy Fibers; Hippocampus (Brain); In Vitro; Intellectual functioning disability; Knockout Mice; Label; Lead; Learning; Link; Mediating; Memory; Mental disorders; Molecular; Mutation; Neurodevelopmental Disorder; Neurons; Neurosciences; Output; Patients; Play; Point Mutation; Property; Protein Isoforms; RNA Splicing; Research; Resolution; Role; Scanning Electron Microscopy; Signal Transduction; Specificity; Structure; Susceptibility Gene; Synapses; Synaptic plasticity; Syndrome; Testing; Training; Vertebral column; base; density; dentate gyrus; gamma-Aminobutyric Acid; in vivo; interest; mossy fiber; nervous system disorder; neural circuit; neurotransmission; novel; overexpression; postsynaptic; presynaptic; relating to nervous system; research study; synaptic function; synaptogenesis

DESCRIPTION (provided by applicant): Synapses are specialized neuronal junctions required for nearly all neurotransmission in the brain. Most synapses contain many of the same basic molecular components but there are also specificity molecules that instruct neurons to make different types of synapses with different types of synaptic partners. Thus far, research has largely focused on understanding basic molecules found at all synapses and we have little mechanistic understanding of how neurons develop specificity. Nonetheless, mutations in putative synaptic specificity molecules are emerging as key susceptibility genes for cognitive disorders. In particular, mutations in the gene Kirrel3 are repeatedly found in patients with intellectual disabilities but the role of Kirrel3 in synapse formation in the mammalian brain has not been investigated. Here, we present evidence that Kirrel3 is a novel synaptic specificity molecule at hippocampal mossy fiber synapses. In this proposal, we will define the role of Kirrel3 in mossy fiber synapse formation at an ultrastructural level, elucidate Kirrel3 signaling mechanisms, and its role in learning-dependent synaptic plasticity. Importantly, we will determine whether Kirrel3 point mutations identified in patients with autism and intellectual disability have an attenuated synaptic function. Our results will increase our understanding in several intersecting areas of neuroscience including the cellular basis of neurological disorders, learning and memory, and molecular mechanisms of synaptic specificity.

描述（由申请人提供）：突触是大脑中几乎所有神经传递所需的专门神经元接头。大多数突触包含许多相同的基本分子成分，但也有特异性分子指导神经元与不同类型的突触伴侣形成不同类型的突触。到目前为止，研究主要集中在了解所有突触中发现的基本分子上，我们对神经元如何产生特异性的机制了解甚少。尽管如此，假定的突触特异性分子突变正在成为认知障碍的关键易感基因。特别是，在智力残疾患者中反复发现Kirrel3基因突变，但尚未研究Kirrel3在哺乳动物大脑突触形成中的作用。在这里，我们提出的证据表明，Kirrel3是一种新的突触特异性分子在海马苔藓纤维突触。在这个提议中，我们将定义Kirrel3在苔藓纤维突触形成的超微结构水平上的作用，阐明Kirrel3的信号转导机制，以及它在学习依赖性突触可塑性中的作用。重要的是，我们将确定在自闭症和智力残疾患者中发现的Kirrel3点突变是否具有减弱的突触功能。我们的研究结果将增加我们在神经科学的几个交叉领域的理解，包括神经系统疾病的细胞基础，学习和记忆，以及突触特异性的分子机制。