Genetic modulation of synaptic development and maintenance

描述(申请人提供)：对突触连接的精确控制是协调神经功能的关键。突显这一重要性的是，各种神经和神经精神障碍--包括癫痫、智力残疾、自闭症和精神分裂症--被认为至少部分源于突触发生和维持的变化。预防和治疗这些疾病的新方法将取决于对发育中的神经系统指定和重塑突触的机制的更全面的理解。有趣的是，这些障碍中的许多在发病率和严重程度上都表现出明显的性别偏见，这表明神经连接的性别特有属性可能有助于它们的病因。在这里，我们利用最近描述的线虫尾部感觉回路中的性别二型性来识别突触的指定和维持根据个体的生物性别进行调节的机制。在这个探索性的试点项目中，我们的目标有两个。首先，我们将开发使用最近描述的荧光标记策略的工具，以允许在活的线虫的尾部感觉回路中可视化有性二态连接。其次，我们将使用这些试剂来提出几个探索性问题，这些问题将使我们能够产生具体的、可测试的机械论假说。特别是，我们将研究性二型性建立的时间，并将确定特定的细胞焦点，通过这些细胞焦点，遗传性调节突触发生。最终，这一探索性项目将为产生关于分子机制的假说提供基础，这些假说可能有助于理解整个动物界的性二型神经连接和电路功能。

DESCRIPTION (provided by applicant): The precise control of synaptic connectivity is essential to coordinated neural function. Underscoring this importance, a variety of neurological and neuropsychiatric disorders -including epilepsy, intellectual disability, autism and schizophrenia-are thought to arise at least in part from alterations in synaptogenesis and maintenance. New approaches to the prevention and treatment of these disorders will depend on a fuller understanding of the mechanisms by which the developing nervous system specifies and remodels synapses. Interestingly, many of these disorders exhibit pronounced sex bias in incidence and severity, suggesting that sex-specific properties of neural connectivity could contribute to their etiology. Here, we take advantage of recently described sexual dimorphisms in tail sensory circuitry of the nematode C. elegans to identify mechanisms by which synapse specification and maintenance are modulated according to an individual's biological sex. In this exploratory pilot project, our goals are two-fold. First, we will develop tools using a recently-described fluorescent labeling strategy to allow the visualization of sexually dimorphic connectivity in tail sensory circuitry in living nematodes. Second, we will use these reagents to ask several exploratory questions that will allow us to generate specific, testable mechanistic hypotheses. In particular, we will study the timing with which sexual dimorphisms are established and will identify specific cellular foci through which genetic sex modulates synaptogenesis. Ultimately, this exploratory project will provide a basis for generating hypotheses about molecular mechanisms that may contribute to understanding sexually dimorphic neural connectivity and circuit function across the animal kingdom.