The role of synaptonuclear signaling proteins in long-term hippocampal synaptic plasticity

项目摘要： 突触可塑性是神经系统的基本原理，并且是许多神经生物学机制的基础。 包括神经发育、感觉处理和记忆储存的过程。新基因转录 是持久的可塑性所必需的，这种转录的要求表明， 受刺激的突触必须通过突触核信号传导到达细胞核。一个这样的机制， 突触核信号传导是长期可塑性的关键，是信号传导的物理移位 从突触到细胞核的蛋白质虽然已知有几十种蛋白质会发生活性- 依赖于突触到核的易位，很少有工作已经做了系统地确定 进行这种易位的蛋白质群体。此外，对基因表达所知甚少， 这些突触核信号蛋白启动的程序。该项目旨在：1）描述 典型突触核信号蛋白CREB调节转录的基因调节作用 辅激活因子1（CRTC 1）;和2）系统地鉴定经历突触-细胞核结合的蛋白质。 在可塑性过程中的易位。对于第一个目标，电生理学将用于表征晚期 CRTC 1急性海马脑片的长时程增强（LTP）和长时程抑制（LTD） 条件性基因敲除小鼠研究CRTC 1在持久可塑性中的功能。这些研究报告将 与RNA测序互补，以确定CRTC 1在转录程序中的作用， 产生长期的可塑性。在第二个目标，新的突触核信号蛋白将被确定 使用生化筛选。简而言之，质谱法将用于识别突触蛋白， 与进口β1核运输复合体结合，因此可能是运往核运输的货物。 导入.候选蛋白质将在突触可塑性的背景下进行研究。识别新的蛋白质， 从突触到细胞核的易位将提供对在突触中易位的信号类型的洞察。 可塑性，以及这些突触核信号蛋白的身份和功能将提供深入了解 可塑性过程中基因表达的调节。突触可塑性广泛涉及神经系统 功能和功能障碍，从而解决这些关于突触可塑性的基本问题 将提供深入了解许多神经和神经精神疾病的机制。

Project Abstract: Synaptic plasticity is a fundamental principle of the nervous system and underlies many neurobiological processes including neurodevelopment, sensory processing, and memory storage. New gene transcription is required for long-lasting plasticity, and this requirement for transcription indicates that signals from stimulated synapses must reach the nucleus via synaptonuclear signaling. One such mechanism of synaptonuclear signaling that is essential for long-term plasticity is the physical translocation of signaling proteins from the synapse to the nucleus. While a few dozen proteins are known to undergo activity- dependent synapse-to-nucleus translocation, little work has been done to systematically identify the population of proteins that undergo this translocation. Moreover, little is known about the gene expression programs that these synaptonuclear signaling proteins initiate. This project aims to: 1) Characterize the gene regulatory role of an exemplar synaptonuclear signaling protein, CREB-Regulated Transcriptional Coactivator 1 (CRTC1); and 2) Systematically identify proteins that undergo synapse-to-nucleus translocation during plasticity. For the first aim, electrophysiology will be used to characterize late-phase long-term potentiation (LTP) and long-term depression (LTD) in acute hippocampal slices from CRTC1 conditional knockout mice to study the function of CRTC1 in long-lasting plasticity. These studies will be complemented with RNA sequencing to determine the role of CRTC1 in the transcriptional programs that give rise to long-term plasticity. In the second aim, novel synaptonuclear signaling proteins will be identified using a biochemical screen. In brief, mass spectrometry will be used to identify synaptic proteins that are bound to the importin β1 nuclear transport complex and are therefore likely to be cargo destined for nuclear import. Candidate proteins will be studied in the context of synaptic plasticity. Identifying novel proteins that translocate from synapse to nucleus will provide insight into the types of signals that translocate during plasticity, and the identity and function of these synaptonuclear signaling proteins will provide insights into the regulation of gene expression during plasticity. Synaptic plasticity is widely involved in neurological function and dysfunction, and therefore addressing these fundamental questions about synaptic plasticity will provide insight into the mechanisms underlying many neurological and neuropsychiatric disorders.