The role of CASPR2 in central oxytocin system development

目的：催产素被认为是哺乳动物社会依恋最重要的调节因子。拟议的研究计划将调查中央催产素系统的发展，重点是神经粘附蛋白CASPR2，对系统的发展和功能至关重要。背景和理由：催产素在社会行为的许多方面发挥着重要作用，包括母亲依恋和与非亲属的社会凝聚力。它由下丘脑的神经元合成，作用于整个中枢神经系统的神经元。催产素系统在生命早期的发展对于在青春期和成年期建立正常的社会行为范围至关重要。尽管如此重要，但调节中枢催产素系统发育的神经机制尚未明确。最近的研究表明，神经粘附蛋白CASPR2参与了催产素系统的发育。CASPR2参与树突发育、突触发生和K+通道聚集。此外，基因工程缺乏CASPR2的小鼠大脑催产素水平较低，社会行为减少。然而，仅仅是恢复这些小鼠的催产素神经元的尖峰活动，就可以拯救它们的社会行为。这些发现共同建立了CASPR2，催产素系统功能和社会行为之间的联系。尽管有这些联系，CASPR2如何调节中枢催产素系统的发育和功能仍然未知。目的与方法：1.确定CASPR2依赖的分子和细胞机制，调节中枢催产素系统的结构和功能发育。我将测试CASPR2有助于建立催产素神经元的最佳尖峰速率的假设，从而确保足够的催产素输送来支持社会行为。我将研究CASPR2缺乏小鼠催产素神经元的电生理学特征和形态学，并与野生型进行比较。2.确定CASPR2在发育或成年期的表达是否是中枢催产素系统和正常社会行为的正常功能所必需的。我将测试的假设，CASPR2表达在早期发展是至关重要的调节中央催产素系统的发展。我将使用一种突变小鼠系，旨在选择性地挽救CASPR2在早期发育或成年期的表达，并研究它是否挽救催产素神经元的细胞形态和电生理特性，以及CASPR2缺乏小鼠的社会障碍。结果：这项工作将扩大我们目前对中枢催产素系统的发展和功能的理解。这项研究的发现将为社会行为发展的分子和细胞机制提供新的见解，并进一步确定关键时间点，这可能有利于设计社会发育迟缓婴儿的干预策略。

Objectives: Oxytocin is recognized as the most important mediator of social attachment in mammals. The proposed research program will investigate development of the central oxytocin system focusing on a neural adhesion protein, CASPR2, critical for the system's development and function. Background & Rationale: Oxytocin plays a well-established role in many aspects of social behaviour, including maternal attachment and social cohesion with non-kin. It is synthesized by neurons in the hypothalamus and acts on neurons throughout the central nervous system. The development of the oxytocin system during early life is crucial for establishing a normal range of social behaviours in adolescence and adulthood. Despite this importance, the neural mechanisms that regulate the development of the central oxytocin system are not well-defined. Recent studies have implicated a neural adhesion protein, CASPR2, in the development of the oxytocin system. CASPR2 is involved in dendritic development, synaptogenesis, and K+ channel clustering. Furthermore, mice genetically engineered to lack CASPR2 have low brain oxytocin levels and reduced social behaviour. Simply restoring spiking activity to oxytocin neurons in those mice, however, can rescue their social behaviour. Together those findings establish links between CASPR2, oxytocin system functioning, and social behaviour. Despite those links, how CASPR2 regulates development and function of the central oxytocin system remains unknown. Aims & Methods: 1. Identify the CASPR2-dependent molecular and cellular mechanisms that regulate structural and functional development of the central oxytocin system. I will test the hypothesis that CASPR2 contributes to establishing the optimal spike rate for of oxytocin neuron, thereby ensuring sufficient delivery of oxytocin to support social behaviour. I will examine the electrophysiological characteristics and morphology of oxytocin neurons in CASPR2-lacking mice and compare to wildtypes. 2. Determine whether CASPR2 expression during development or adulthood is necessary for proper function of the central oxytocin system and normal social behaviour. I will test the hypothesis that CASPR2 expression during early development is critical for regulating central oxytocin system development. I will use a mutant mouse line designed to selectively rescue CASPR2 expression during early development or adulthood, and examine whether it rescues the cellular morphology and electrophysiological properties in oxytocin neurons, as well as social impairments in CASPR2-lacking mice. Outcome: The proposed work will expand our current understanding on the development and function of the central oxytocin system. Findings from this study will provide new insights into the molecular and cellular mechanisms of social behaviour development and further define the critical time point(s), which may be beneficial to designing intervention strategies for infants with social developmental delays.