Understanding the triggers of homeostatic synaptic scaling

摘要 动态平衡可塑性的机制确保细胞在 生理上相关的窗口。这种形式的可塑性可防止细胞陷入沉默或 变得极度兴奋。对兴奋性活动的动态平衡控制对神经来说至关重要。 系统功能，如癫痫等情况的严重性所表明的，其中这种动态平衡 是不会实现的。动态平衡可塑性被认为是网络行为健壮性的基础， 允许在扰动后恢复行为。在过去的15年里，经历了戏剧性的 关于体内平衡可塑性的研究正在兴起，现在已经证明了多种机制，其中 有助于在扰动后的尖峰活动的弹性。到目前为止研究最多的 动态平衡可塑性的机制被称为突触伸缩。当活动达到峰值时 培养的神经元被阻断几天后，细胞的所有兴奋性突触都会加强，或者扩大。 目前该领域的想法表明，突触伸缩是由刺激性活动减少触发的， 然后，它会恢复正常的峰值水平。在这项提案中，我们挑战这一非常基本的观点，但 很大程度上未经检验的假设。我们假设突触伸缩是由下丘脑 个体突触的突触传递以稳态方式维持突触传递，而不是 而不是作为一种自我平衡调节细胞尖峰活动的手段。我们将使用以下工具验证这一假设 光遗传学和培养神经元的多电极阵列记录相结合。我们会问 在AIM 1中，兴奋性上调是由谷氨酸能传递减少触发的？然后我们就会请进来 目的2兴奋性降低是否由谷氨酸能传递增加所触发？在《目标3》中，我们将 确定尖峰或传输中的变化是否会触发GABA能伸缩。如果结果是有利的 神经传递作为突触伸缩的触发器，这可能会在 突触的焦点从目前普遍存在的以活动为中心的感知中转移。这 Proposal将使用允许评估和控制尖峰的新技术的组合 活动水平，以提出有关体内平衡可塑性的根本重要问题。结果将会是 对于了解损伤和疾病后电路的变化具有重要意义。

Abstract Mechanisms of homeostatic plasticity ensure that cells maintain spiking activity levels within a physiologically relevant window. This form of plasticity prevents cells from falling silent or from becoming hyperexcitable. The homeostatic control of spiking activity is critically important to nervous system function, as demonstrated by the severity of conditions like seizure, where such homeostasis is not achieved. Homeostatic plasticity is thought to underlie the robustness of network behavior, and allow for the recovery of behaviors following perturbations. The last 15 years have seen a dramatic rise in studies of homeostatic plasticity, which have now demonstrated multiple mechanisms, which contribute to the resilience of spiking activity following perturbations. By far the most studied mechanism of homeostatic plasticity has been referred to as synaptic scaling. When spiking activity in cultured neurons is blocked for days, all of a cell's excitatory synapses strengthen, or scale up. Current thinking in the field suggests that synaptic scaling is triggered by reduced spiking activity, which then acts to recover normal spiking levels. In this proposal we challenge this very basic, but largely untested assumption. We hypothesize that synaptic scaling is triggered by reductions in synaptic transmission at individual synapses to homeostatically maintain synaptic transmission, rather than as a means to homeostatically regulate a cells spiking activity. We will test this hypothesis using a combination of optogenetics and multi-electrode array recordings of cultured neurons. We will ask in aim 1 excitatory upscaling is triggered by reduced glutamatergic transmission? Then we will ask in aim 2 if excitatory downscaling is triggered by increased glutamatergic transmission? In aim 3 we will determine if alterations in spiking or transmission trigger GABAergic scaling. If the results favor neurotransmission as the trigger for synaptic scaling, this could provide a transformative shift in the focus of synaptic scaling away from the activity-centric perception that is currently pervasive. This proposal will use a combination of new techniques that allow the assessment and control of spiking activity levels to ask fundamentally important questions about homeostatic plasticity. The results will have significant implications for understanding how circuits change following injury and disease.