Genetic modulation of synaptic development and maintenance

描述（由申请人提供）：突触连接的精确控制对于协调神经功能至关重要。强调这一重要性，各种神经和神经精神疾病-包括癫痫，智力残疾，自闭症和精神分裂症-被认为至少部分来自突触发生和维持的改变。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，这些疾病中的许多在发病率和严重程度上表现出明显的性别偏见，这表明神经连接的性别特异性可能有助于其病因。在这里，我们利用最近描述的性二态性尾部感觉回路的线虫C。elegans来确定突触的特化和维持是根据个体的生物性别来调节的机制。在这个探索性的试点项目中，我们的目标是双重的。首先，我们将开发工具，使用最近描述的荧光标记策略，使可视化的性二态连接在尾部感觉回路中的活线虫。其次，我们将使用这些试剂提出几个探索性问题，使我们能够产生具体的，可检验的机制假设。特别是，我们将研究性别二型性建立的时间，并将确定特定的细胞灶，通过遗传性别调节突触发生。最终，这个探索性的项目将为产生有关分子机制的假设提供基础，这些分子机制可能有助于理解整个动物王国的性二态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.