The intellectual disability-associated gene kirrel3 in synapse development

描述（由申请人提供）：突触是大脑中几乎所有神经传递所必需的特殊神经元连接。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示神经元与不同类型的突触伙伴形成不同类型的突触。到目前为止，研究主要集中在理解在所有突触中发现的基本分子，我们对神经元如何发展特异性的机制知之甚少。尽管如此，假设的突触特异性分子的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基因Kirrel3的突变，但尚未研究Kirrel3在哺乳动物大脑突触形成中的作用。在这里，我们提出证据表明Kirrel3是海马苔藓纤维突触中的一种新的突触特异性分子。在本研究中，我们将在超微结构水平上定义Kirrel3在苔藓纤维突触形成中的作用，阐明Kirrel3信号机制及其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。我们的结果将增加我们对神经科学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。

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.