Synapse to Nuclear Signaling During Long-Lasting Neuronal Plasticity

持久神经元可塑性期间突触到核信号传导

• 批准号: 8848886
• 负责人: Kelsey C Martin
• 金额: $ 37.68万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-05 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8848886
• 关键词: Active Biological Transport; Address; Affect; Alzheimer' s Disease; Award; Biological; CREB1 gene; Calcium; Cell Nucleus; Cell physiology; Cells; Cellular biology; Cognition; Cognition Disorders; Cognitive; Complex; Coupled; Coupling; Cyclic AMP; Dendrites; Disease; Dopamine; Event; Funding; Gene Expression; Gene Expression Profile; Gene Targeting; Genetic Transcription; Glutamates; Health; Hippocampus (Brain); Human; Importins; Knockout Mice; Learning; Life; Light; Link; Long-Term Potentiation; Mass Spectrum Analysis; Mediating; Memory; Memory Disorders; Memory Loss; Mental Retardation; Microscopy; Mus; Mutation; Neuromodulator; Neuronal Plasticity; Neurons; Norepinephrine; Nuclear; Nuclear Import; Nuclear Translocation; Pathway interactions; Pattern; Phosphorylation; Post-Translational Protein Processing; Process; Proteins; Proteomics; RNA Sequences; Reagent; Recruitment Activity; Rodent; Role; Signal Transduction; Signaling Molecule; Site; Small Interfering RNA; Stimulus; Synapses; Synaptic plasticity; System; Transcription Coactivator; Travel; age related; cellular imaging; excitatory neuron; experience; gene induction; insight; lens; long term memory; neuronal cell body; neuropsychiatry; neuroregulation; novel; nucleocytoplasmic transport; research study; response; retrograde transport; trafficking; transcription factor; transcriptome sequencing

DESCRIPTION (provided by applicant): Hebbian and homeostatic forms of synaptic plasticity require new gene expression for their persistence. For stimulus-induced alterations in transcription to occur, signals must be relayed from sites of synaptic stimulation to the nucleus. Such long-distance retrograde transport poses a unique set of challenges in neurons, where synapses can be located at great distances from the cell soma and nucleus. Electrochemical and calcium-dependent processes allow for extremely rapid signaling between subcellular compartments in neurons. Studies in a number of systems have also indicated that soluble signaling molecules can be transported from the synapse to the nucleus to effect changes in transcription. This proposal is aimed at elucidating the cell biology of synapse to nuclear signaling during long-lasting, learning-related synaptic plasticity in mouse hippocampal neurons. During the past funding cycle, we characterized a role for importin-mediated active nuclear import of synaptically localized transcription during hippocampal long-term potentiation. Synapse to nuclear transport of transcription factors provides a direct means of coupling synaptic activity with changes in gene expression. We focus this continuation proposal on the synapse to nuclear transport of the CREB regulated transcriptional coactivator CRTC1 during activity-dependent plasticity. We have shown that CRTC1 tracks glutamatergic activity in excitatory neurons to inform the nucleus about synaptic events. It is actively transported into the nucleus from stimulated synapses, and undergoes profound changes in post-translational modification in response to stimulation. Moreover, while glutamatergic stimuli trigger CRTC1 nuclear import, neuromodulatory inputs that elevate intracellular cAMP regulate the persistence of CRTC1 in the nucleus. We have generated a number of reagents to study and manipulate CRTC1 in neurons and now propose to use these to perform an in-depth analysis of the cell biology and function of its synapse to nuclear signaling during long-term synaptic plasticity of mouse hippocampal neurons. Towards this end we propose three specific aims directed at answering three sets of questions: 1) How does CRTC1 travel from synapse to nucleus; 2) How does CRTC1 nuclear import alter gene expression? How do stimulus-induced change in CRTC1 phosphorylation alter its nuclear transport and downstream transcription? and 3) How does neuromodulation regulate CRTC1-mediated gene expression? The answers to these questions will provide insight into the cell biology of learning-related gene expression, and into the particular function of CRTC1. The results of our studies are relevant to a spectrum of neuropsychiatric disorders, and to cognitive disorders (such as mental retardation, Alzheimer's Disease and age-related memory loss) in which long-term memory is impaired.

描述（由申请人提供）：突触可塑性的赫布形式和稳态形式需要新的基因表达来维持其持久性。为了发生刺激诱导的转录改变，信号必须从突触刺激位点传递到细胞核。这种长距离逆行运输对神经元提出了一系列独特的挑战，其中突触可能距离细胞体和细胞核很远。电化学和钙依赖性过程允许神经元亚细胞区室之间极其快速的信号传导。对许多系统的研究还表明，可溶性信号分子可以从突触转运到细胞核，以影响转录的变化。该提案旨在阐明小鼠海马神经元持久的、与学习相关的突触可塑性期间突触到核信号传导的细胞生物学。在过去的资助周期中，我们描述了输入蛋白介导的突触局部转录的主动核输入在海马长期增强过程中的作用。转录因子的突触到核转运提供了将突触活性与基因表达变化耦合的直接方法。我们将这一延续提案的重点放在活性依赖性可塑性过程中 CREB ​​调节的转录共激活因子 CRTC1 的突触到核运输上。我们已经证明 CRTC1 跟踪兴奋性神经元中的谷氨酸能活性，以向细胞核通报突触事件。它被积极地输送到 来自受刺激突触的细胞核，并在响应刺激的翻译后修饰中经历深刻的变化。此外，虽然谷氨酸刺激触发 CRTC1 核输入，但提高细胞内 cAMP 的神经调节输入调节 CRTC1 在细胞核中的持续存在。我们已经产生了许多试剂来研究和操纵神经元中的 CRTC1，现在建议使用这些试剂来深入分析小鼠海马神经元长期突触可塑性过程中突触与核信号传导的功能。为此，我们提出了三个具体目标，旨在回答三组问题：1）CRTC1如何从突触到细胞核； 2) CRTC1核输入如何改变基因表达？刺激诱导的 CRTC1 磷酸化变化如何改变其核运输和下游转录？ 3) 神经调节如何调节 CRTC1 介导的基因表达？这些问题的答案将有助于深入了解学习相关基因表达的细胞生物学以及 CRTC1 的特定功能。我们的研究结果与一系列神经精神疾病以及长期记忆受损的认知障碍（例如精神发育迟滞、阿尔茨海默病和与年龄相关的记忆丧失）相关。