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

项目总结 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。这个 这些特殊连接的功能障碍被认为是认知能力下降的一个原因。近期 研究结果有力地表明，海马区突触可塑性的逐渐损害与 随着年龄的增长和神经退行性疾病的进展而导致的认知衰退。因此，它是 进一步阐明海马区突触可塑性的机制以更好地理解学习 并开发治疗记忆力衰退的有效方法。兴奋性突触主要是 位于被称为树突棘的神经元树突的肌动蛋白丰富的突起上。我们之前建立了 Rac1特异性鸟核苷酸交换因子Tiam1作为脊椎的重要调节因子 培养细胞中NMDA型谷氨酸受体(NMDAR)对rac1信号的作用 海马神经元。在人类和啮齿类动物的大脑中，Tiam1在齿状回(DG)中都很丰富。 在整个生命过程中，海马体的亚区。然而，它在哺乳动物大脑中的功能作用，特别是 在成年人中，这一点尚不清楚。我们最近的初步数据表明，Tiam1在调节突触方面发挥着持续的作用 DG内的可塑性。我们发现成年小鼠前脑兴奋性神经元中Tiam1基因的缺失 DG颗粒神经元NMDAR介导的电流和DG的突触可塑性增强。令人惊讶的是， Tiam1基因缺失的小鼠在海马区依赖的学习和记忆中表现出增强的表现。 根据我们的初步发现，我们认为rac1-egf Tiam1可能是一种理想的分子工具 探索在海马区内维持适当突触可塑性的机制 也是治疗涉及记忆障碍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，病毒介导的依赖活动的神经元标记， 分子和细胞生物学、电生理学和行为分析，我们建议确定 Tiam1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：(1)阐明Tiam1限制突触可塑性的机制；(2)确定Tiam1在突触可塑性中的作用 海马区依赖的学习和记忆。这项拟议研究的目标是揭示关键的分子和 限制成年大脑中海马区可塑性和学习记忆的细胞机制 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.