Role of the Rac1-GEF Tiam1 in Synaptic Plasticity and Hippocampal-Dependent Learning and Memory

项目摘要 我们学习和形成记忆的能力依赖于兴奋性突触的精确和动态调节。的 这些专门连接的功能障碍强烈暗示为认知衰退的因果因素。最近 研究结果强烈提示海马突触可塑性的逐渐损伤与 认知能力下降伴随着衰老和神经退行性疾病的进展。照经上所 为了更好地理解学习，有必要进一步阐明海马突触可塑性的机制 和记忆，并开发有效的方法来治疗记忆衰退。兴奋性突触主要是 位于称为树突棘的神经元树突的富含肌动蛋白的突起上。我们以前建立了 Rac 1特异性鸟嘌呤核苷酸交换因子（GEF）Tiam 1作为脊柱的重要调节因子 将NMDA型谷氨酸受体（NMDAR）活性与Rac 1信号传导偶联的形态发生在培养的 海马神经元在人类和啮齿动物的大脑中，Tiam 1在齿状回（DG）中富集。 海马的亚区。然而，它在哺乳动物大脑中的功能作用， 成年人，尚不清楚。我们最近的初步数据表明Tiam 1在调节突触的形成中起着持续的作用。 DG内的可塑性。我们发现成年小鼠前脑兴奋性神经元中Tiam 1的缺失 增强DG颗粒神经元的NMDAR介导电流和DG的突触可塑性。令人惊讶的是， Tiam 1基因敲除小鼠在海马依赖性学习和记忆方面也表现出增强的表现。 基于我们的初步研究结果，我们认为Rac 1-GEF Tiam 1可以作为一种理想的分子工具 用于探索负责维持海马内适当突触可塑性的机制， 以及作为治疗涉及记忆损伤的疾病的潜在治疗靶点。使用切割- 边缘技术，包括高分辨率显微镜，病毒介导的活动依赖性神经元标记， 分子和细胞生物学，电生理学和行为分析，我们建议确定的作用 Tiam 1在成人大脑中控制适当的突触可塑性和认知功能。具体来说，我们建议 目的是（1）阐明Tiam 1限制突触可塑性的机制，（2）确定Tiam 1在 依赖于大脑的学习和记忆。这项研究的目的是揭示关键的分子和 细胞机制，限制海马可塑性和学习和记忆在成人大脑，并有助于 确定新的治疗靶点以增强认知功能。

PROJECT SUMMARY Our ability to learn and form memories relies on the precise and dynamic regulation of excitatory synapses. The dysfunction of these specialized connections is strongly implicated as a causal factor of cognitive decline. Recent findings strongly suggest a connection between the gradual impairment of hippocampal synaptic plasticity and the cognitive decline that accompanies aging and the progression of neurodegenerative diseases. Thus, it is imperative to further elucidate the mechanisms of hippocampal synaptic plasticity to better understand learning and memory and to develop effective approaches to treat memory decline. Excitatory synapses are primarily located on actin-rich protrusions of neuronal dendrites known as dendritic spines. We previously established the Rac1-specific guanine nucleotide exchange factor (GEF) Tiam1 as an important regulator of spine morphogenesis that couple’s NMDA-type glutamate receptor (NMDAR) activity to Rac1 signaling in cultured hippocampal neurons. In both the human and rodent brains, Tiam1 is enriched in the dentate gyrus (DG) subregion of the hippocampus throughout life. However, its functional role in the mammalian brain, particularly in adults, is unclear. Our recent preliminary data suggests that Tiam1 plays an ongoing role in regulating synaptic plasticity within the DG. We found that the deletion of Tiam1 from excitatory neurons in the adult mouse forebrain enhanced NMDAR-mediated currents in DG granule neurons and synaptic plasticity in the DG. Surprisingly, Tiam1 null mice also demonstrated enhanced performance in hippocampal-dependent learning and memory. Based on our preliminary findings, we propose that the Rac1-GEF Tiam1 may serve as an ideal molecular tool for exploring the mechanisms responsible for maintaining proper synaptic plasticity within the hippocampus as well as a potential therapeutic target for the treatment of disorders involving memory impairments. Using cutting- edge techniques that include high-resolution microscopy, viral-mediated activity-dependent neuronal labeling, molecular and cellular biology, electrophysiology, and behavioral analyses, we propose to determine the role of Tiam1 in the control of proper synaptic plasticity and cognitive function in the adult brain. Specifically, we propose to (1) elucidate the mechanisms by which Tiam1 restricts synaptic plasticity and (2) determine Tiam1’s role in hippocampal-dependent learning and memory. The goals of the proposed study are to reveal key molecular and cellular mechanisms that limit hippocampal plasticity and learning and memory in the adult brain and help to identify new therapeutic targets to enhance cognitive function.