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

Rac1-GEF Tiam1 在突触可塑性和海马依赖性学习和记忆中的作用

• 批准号: 10403424
• 负责人: Francisco Alejandro Blanco
• 金额: $ 4.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-17 至 2024-05-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403424
• 关键词: Actins; Acute; Address; Adhesions; Adult; Affect; Aging; Agonist; Animals; Behavioral; Biochemical; Brain; Cells; Cognitive; Cytoplasmic Granules; Data; Dendrites; Dendritic Spines; Development; Disease; Electrophysiology (science); Endocytosis; Excitatory Synapse; Extracellular Matrix; F-Actin; Functional disorder; Genetic; Glutamate Receptor; Goals; Guanine; Guanine Nucleotide Exchange Factors; Hippocampus (Brain); Human; Impaired cognition; Impairment; Information Storage; Knockout Mice; Label; Learning; Life; Long-Term Potentiation; Mediating; Memory; Memory Loss; Memory impairment; Microfilaments; Microscopy; Modeling; Molecular; Molecular and Cellular Biology; Morphogenesis; Morphology; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Neurons; Nucleotides; Performance; Play; Process; Prosencephalon; RNA Interference; Receptor Signaling; Regulation; Resolution; Rodent; Role; Signal Transduction; Signal Transduction Pathway; Surface; Synapses; Synaptic plasticity; Techniques; Testing; Therapeutic; Vertebral column; Viral; Work; age related; aged; base; cognitive enhancement; cognitive function; dentate gyrus; excitatory neuron; flexibility; granule cell; information processing; knock-down; memory retention; new therapeutic target; prevent; receptor function; receptor internalization; response; skills; synaptic function; therapeutic target; tool

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.

项目概要 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。 这些专门连接的功能障碍与近期认知能力下降密切相关。 研究结果强烈表明海马突触可塑性的逐渐受损与 伴随衰老和神经退行性疾病进展的认知能力下降。 必须进一步阐明海马突触可塑性的机制，以更好地理解学习 和记忆并开发治疗记忆衰退的有效方法主要是兴奋性突触。 位于神经树突富含肌动蛋白的突起上，称为树突棘。 Rac1 特异性鸟嘌呤核苷酸交换因子 (GEF) Tiam1 作为脊柱的重要调节因子 培养物中 NMDA 型谷氨酸受体 (NMDAR) 活性与 Rac1 信号传导耦合的形态发生 在人类和啮齿类动物的海马神经元中，Tiam1 均富含于齿状回 (DG)。 然而，它在哺乳动物大脑中的功能作用，尤其是在整个生命过程中。 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。 我们发现成年小鼠前脑兴奋性神经元中 Tiam1 的缺失。 令人惊讶的是，DG 颗粒神经元中 NMDAR 介导的电流和突触可塑性增强。 Tiam1 缺失小鼠还表现出海马依赖性学习和记忆能力的增强。 根据我们的初步研究结果，我们建议 Rac1-GEF Tiam1 可以作为理想的分子工具 探索负责维持海马内适当突触可塑性的机制 以及治疗涉及记忆障碍的疾病的潜在治疗靶标。 边缘技术，包括高分辨率显微镜、病毒介导的活性依赖性神经元标记、 分子和细胞生物学、电生理学和行为分析，我们建议确定 具体来说，我们建议 Tiam1 控制成人大脑中适当的突触可塑性和认知功能。 (1) 阐明 Tiam1 限制突触可塑性的机制，以及 (2) 确定 Tiam1 在 本研究的目标是揭示海马依赖性学习和记忆。 限制成人大脑海马可塑性以及学习和记忆的细胞机制，有助于 确定新的治疗靶点以增强认知功能。