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。 和由高危精神分裂症（SCZ）突变诱导的突触表型，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 这些表型与人类患者SCZ相关症状的关系，只能是 在小鼠身上进行了实验，但在人类身上没有。因此，这一项目是实现以下目标的重要组成部分： 本申请的总体目标是确定SCZ的不同高风险突变是否 产生突触表型，这些表型表现出共性，以及未来是否筛选 可以开发改善这种表型的治疗剂。这些目标的内在要求是，不仅需要 验证跨平台表型的可重复性，但也将这些表型与症状相关联 在SCZ观察。项目2将重点放在小鼠神经元上，这些神经元的突变构成了 在其他项目中对人类神经元的研究，即Nrxn 1杂合和纯合缺失， 最小临界22q11.2缺失和16p11.2重复和缺失。三个具体目标 该项目将在斯坦福大学的协调下以合作的方式进行（汤姆·S·霍夫和 Marius Wernig），罗格斯大学（Zhiping Pang），美国国家航空航天局（U。《阿林纳蒂》（布鲁斯·阿罗诺饰）， Eli Lilly（John Isaac）这三个具体目标是：（1）确定神经元和突触 携带Nrxn 1基因缺失的初级内侧前额叶皮层神经元的表型， 22q11.2缺失，或16p11.2重复或缺失，（2）以测试是否从小鼠产生iN细胞 来源于突变小鼠的胚胎成纤维细胞（MEF）和iPS细胞复制各自的表型， 原代神经元中的突变，以及（3）为了确定Nrxn 1基因缺失的影响， 22q11.2缺失和16p11.2复制对大鼠脑片原位神经元突触特性的影响 内侧前额叶皮层这三个具体目标将共同利用跨学科的方法来研究SCZ 病理生理学在小鼠模型的障碍，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元功能影响的验证。它们将使 不仅验证了项目1和3中使用人类iN细胞获得的结果，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.