Drosophila as an Experimental Model for Epilepsy

描述（由申请人提供）：神经元发育和突触形成需要协调的信号传导以协调突触连接的突触前和突触后成熟。长期的目标是确定新的活动依赖性突触生长机制，触发癫痫发作和神经元可塑性，我们建议使用果蝇作为一个模型系统，用于表征增强神经元活动驱动突触生长的分子机制。我们将描述活动依赖性突触生长信号的接收和传输是如何发生在突触前末梢的一个专门区域，称为活动周区。特别是，我们将确定F-BAR蛋白如何在活动区调节肌动蛋白组装和膜变形，以触发内吞作用和活动依赖性方式激活的突触生长信号受体的贩运。人们普遍认识到，癫痫状态期间过度的神经元活动加强了突触布线电路，导致不稳定的复发性连接，使癫痫发作更加频繁和严重。对活动依赖性重新布线机制的理解在儿科癫痫中也很重要，其中不成熟和成熟大脑之间的差异导致癫痫发作的独特病理生理学和后果。未成熟大脑的兴奋性增加会导致神经元连接的不可逆改变。在这里，我们建议利用宿主的遗传操作，在果蝇的特征的细胞和分子机制，增强神经元的活动耦合到修改突触连接和电路重新布线。公共卫生相关性：在癫痫发作期间，大脑功能和连通性的活动依赖性变化响应于过度的神经元放电而发生。癫痫状态期间过度的神经元活动加强了突触布线电路，导致不稳定的反复连接，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，探讨癫痫期间增强神经元活动与突触连接修改的细胞和分子机制。

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.