Effects of psychosis high-risk mtations on mouse synaptic function

在这个项目2中，我们建议研究小鼠神经元，以便在模型系统中更好地定义神经元 和突触表型诱发的高危精神分裂症(SCZ)突变，以测试小鼠是否 表型与在人类神经元中观察到的表型一致(跨平台验证)，并探索 这种表型与人类患者SCZ相关症状的关系，实验只能是 在老鼠身上进行，但不在人类身上进行。因此，该项目是追求 该应用程序的主要目标是确定SCZ的不同高危突变 产生突触表型，其中这些表型表现出共性，以及未来对 可以开发出改善这种表型的治疗方法。这些目标所固有的是不仅需要 验证跨平台的表型的重复性，但也要将这些表型与症状联系起来 在SCZ观察到。项目2将重点放在小鼠神经元上，这些突变构成了 在其他项目中对人神经元的研究，即NRXN1杂合和纯合子缺失， 最小的关键22q11.2缺失，以及16p11.2复制和缺失。的三个具体目标 该项目将在斯坦福大学(汤姆·S、�dhof和 作者声明：The University of Cincinnatti(Bruce Aronow)； 还有礼来公司(约翰·艾萨克饰)。这三个具体目标是：(1)确定神经元和突触 携带NRXN1基因缺失的初级内侧前额叶皮质神经元的表型，最小临界 22q11.2缺失，或16p11.2重复或缺失，(2)检测小鼠产生的细胞中是否 来自突变小鼠的胚胎成纤维细胞(MEF)和iPS细胞复制各自的表型 初级神经元的突变，以及(3)确定NRXN1基因缺失的影响，最小关键 22q11.2缺失和16p11.2重复对大鼠脑片原位神经元突触特性的影响 内侧前额叶皮质。这三个具体目标将利用跨学科的方法来研究SCZ。 在小鼠模型中的病理生理学障碍，并提供垂直和水平整合的交叉 SCZ相关高危突变对小鼠神经功能影响的验证。他们将使 不仅验证了在项目1和3的细胞中使用人类获得的结果，而且还促进了 将这些结果转化为理解SCZ相关行为变化的概念性框架。

In this Project 2, we propose to study mouse neurons in order to better define in a model system the neuronal and synaptic phenotypes induced by high-risk schizophrenia (SCZ) mutations, to test whether the mouse phenotypes concur with those observed in human neurons (cross-platform validation), and to explore the relation of such phenotypes to SCZ-associated symptoms in human patients, experiments that can only be performed in mice but not in humans. Thus, this project is an essential component for the pursuit of the overarching goals of this application, which are to determine whether different high-risk mutations for SCZ produce a synaptic phenotype, where such phenotypes exhibit commonalities, and whether future screens for therapeutics to ameliorate such phenotypes can be developed. Inherent in these goals is the need not only to validate the reproducibility of phenotypes across platforms, but also to relate such phenotypes to symptoms observed in SCZ. Project 2 will focus in mouse neurons on the same mutations that constitute the focus of the studies on human neurons in the other projects, namely the Nrxn1 heterozygous and homozygous deletions, the minimal critical 22q11.2 deletion, and the 16p11.2 duplications and deletions. The three specific aims of this project will be carried out in a collaborative fashion coordinated by Stanford University (Tom S�dhof and Marius Wernig), with contributions by Rutgers University (Zhiping Pang), the U. of Cincinnatti (Bruce Aronow), and Eli Lilly (John Isaac). These three specific aims are: (1) To determine the neuronal and synaptic phenotypes of primary medial prefrontal cortex neurons that carry Nrxn1 gene deletions, the minimal critical 22q11.2 deletion, or the 16p11.2 duplication or deletion, (2) to test whether iN cells produced from mouse embryonic fibroblasts (MEFs) and iPS cells derived from mutant mice replicate the phenotype of the respective mutations in primary neurons, and (3) to determine the effects of the Nrxn1 gene deletions, the minimal critical 22q11.2 deletion, and the 16p11.2 duplication on synaptic properties of neurons in situ in brain slices of the medial prefrontal cortex. Together, the three specific aims will utilize an interdisciplinary approach to study SCZ pathophysiology in mouse models of the disorder, and provide vertically and horizontally integrated cross- validations of the effects of SCZ-associated high-risk mutations on neuronal function in mice. They will enable not only validation of the results obtained with human iN cells in Projects 1 and 3, but also facilitate a translation of such results into a conceptual framework for understanding SCZ-associated behavioral changes.