Drosophila as an Experimental Model for Epilepsy

描述(申请人提供)：神经元发育和突触形成需要协调信号来协调突触连接的突触前和突触后成熟。为了识别由癫痫发作和神经元可塑性触发的新的活性依赖的突触生长机制，我们建议使用果蝇作为一个模型系统来表征神经元活性增强驱动突触生长的分子机制。我们将描述依赖活动的突触生长信号的接收和传输是如何在突触前终末的一个特殊区域发生的，称为周围活动区。特别是，我们将确定F-bar蛋白如何在周围活动区调节肌动蛋白组装和膜变形，以活动依赖的方式触发内吞和激活的突触生长信号受体的运输。人们普遍认识到，癫痫状态下过度的神经元活动会加强突触线路，导致不稳定的经常性连接，从而使癫痫发作更加频繁和严重。对依赖活动的重新连接机制的理解在儿童癫痫中也很重要，在儿童癫痫中，未成熟和成熟大脑之间的差异导致独特的病理生理和癫痫发作的后果。未成熟大脑中兴奋性的增加会导致神经元连接的不可逆转的改变。在这里，我们建议利用果蝇中可用的一系列遗传操作来表征细胞和分子机制，通过这些机制，增强的神经元活动与突触连接和电路重新连接的改变相耦合。与公共健康相关：在癫痫发作期间，大脑功能和连接性的活动依赖变化是对过度神经元放电的反应。癫痫状态下过度的神经元活动会加强突触线路，导致不稳定的经常性连接，使癫痫发作更加频繁和严重。我们建议使用果蝇作为一个模型系统来探索神经元活动增强与突触连接改变相耦合的细胞和分子机制。

DESCRIPTION (provided by applicant): Neuronal development and synapse formation requires coordinated signaling to orchestrate pre- and post-synaptic maturation of synaptic connections. With the long-term goal of identifying novel activity-dependent synaptic growth mechanisms that are triggered by seizures and neuronal plasticity, we propose to use Drosophila as a model system for characterizing the molecular mechanisms by which enhanced neuronal activity drives synaptic growth. We will characterize how the reception and transmission of activity-dependent synaptic growth signals occurs at a specialized region of the presynaptic terminal known as the periactive zone. In particular, we will determine how F-BAR proteins function at periactive zones to modulate actin assembly and membrane deformation to trigger endocytosis and trafficking of activated synaptic growth signaling receptors in an activity-dependent fashion. It is widely appreciated that excessive neuronal activity during epileptic states reinforces synaptic wiring circuits that lead to unstable recurrent connections that make seizure attacks more frequent and severe. An understanding of activity-dependent rewiring mechanisms is also important in pediatric epilepsy, where differences between the immature and mature brain result in unique pathophysiology and consequences of seizures. Increased excitability in the immature brain can lead to irreversible alterations in neuronal connectivity. Here, we propose to take advantage of a host of genetic manipulations available in Drosophila to characterize the cellular and molecular mechanisms by which enhanced neuronal activity couples to modifications of synaptic connectivity and circuit rewiring. PUBLIC HEALTH RELEVANCE: Activity-dependent changes in brain function and connectivity occur in response to excessive neuronal firing during seizure episodes. Excessive neuronal activity during epileptic states reinforces synaptic wiring circuits that lead to unstable recurrent connections that make seizure attacks more frequent and severe. We propose to use Drosophila as a model system to explore the cellular and molecular mechanisms by which enhanced neuronal activity couples to modifications of synaptic connectivity during epilespy.