Synaptic Plasticity In Aging And Neurodegenerative Disorders

衰老和神经退行性疾病中的突触可塑性

• 批准号: 8736521
• 负责人: Mark Mattson
• 金额: $ 84.69万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736521
• 关键词: 4-Aminopyridine; AMPA Receptors; ATP phosphohydrolase; Adult; Affect; Age; Aging; Alzheimer' s Disease; Amyloid; Animal Behavior; Animal Model; Behavioral; Binding Proteins; Biogenesis; Brain; Brain-Derived Neurotrophic Factor; Calcium; Cells; Cessation of life; Cognitive; Cognitive deficits; Complex; Cyclic AMP-Responsive DNA-Binding Protein; Cytoplasmic Granules; Defect; Dendritic Spines; Development; Disease; Event; Excision; Exhibits; Functional disorder; Genes; Genetic; Hippocampus (Brain); Image; Impairment; In Vitro; Knockout Mice; Learning; Lentivirus Vector; Life; Ligands; Long-Term Depression; Long-Term Potentiation; Maintenance; Measurement; Mediating; Memory; Mitochondria; Mitogen-Activated Protein Kinases; Molecular; Molecular Abnormality; Mus; N-Methylaspartate; NCOA2 gene; NF-kappa B; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Nifedipine; Pathology; Patients; Peptides; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Physiologic pulse; Play; Process; Property; Propionic Acids; Receptor Protein-Tyrosine Kinases; Regulation; Role; SNAP receptor; Short-Term Memory; Signal Transduction; Slice; Surface; Swimming; Synapses; Synaptic Transmission; Synaptic plasticity; Technology; Testing; Transgenic Mice; Treatment Efficacy; Vesicle; Wild Type Mouse; age related; azastene; density; dentate gyrus; dietary supplements; hyperphosphorylated tau; in vivo; insight; memory process; middle age; morris water maze; mossy fiber; mutant; neuronal excitability; notch protein; novel; overexpression; patch clamp; postnatal; postsynaptic; preference; receptor; response; synaptic function; synaptogenesis; syntaxin; tau Proteins

The ability of synapses to change their properties in response to environmental demands (synaptic plasticity) is essential for learning and memory. Abnormalities in synaptic plasticity are involved in Alzheimers disease and related disorders. In our continuing efforts to understand the molecular mechanisms involved in synaptic plasticity, in the contexts of aging and neurodegenerative disorders, we have made several major advances. We used Notch antisense transgenic mice that develop and reproduce normally, but exhibit reduced levels of Notch, to demonstrate a role for Notch signaling in synaptic plasticity. Mice with reduced Notch levels exhibit impaired long-term potentiation (LTP) at hippocampal CA1 synapses. A Notch ligand enhances LTP in normal mice and corrects the defect in LTP in Notch antisense transgenic mice. Levels of basal and stimulation-induced NF-kappa B activity were significantly decreased in mice with reduced Notch levels. These findings suggest an important role for Notch signaling in a form of synaptic plasticity known to be associated with learning and memory processes. We found that Notch1 and its ligand Jagged1 are present at the synapse, and that Notch signaling in neurons occurs in response to synaptic activity. In addition, neuronal Notch signaling is positively regulated by Arc/Arg3.1, an activity-induced gene required for synaptic plasticity. In Arc/Arg3.1 mutant neurons, the proteolytic activation of Notch1 is disrupted both in vivo and in vitro. Conditional deletion of Notch1 in the postnatal hippocampus disrupted both long-term potentiation (LTP) and long-term depression (LTD), and led to deficits in learning and short-term memory. Our findings show that Notch signaling is dynamically regulated in response to neuronal activity, Arc/Arg3.1 is a context-dependent Notch regulator, and Notch1 is required for the synaptic plasticity that contributes to memory formation. The synaptic insertion or removal of AMPA receptors (AMPAR) plays critical roles in the regulation of synaptic activity reflected in the expression of long-term potentiation (LTP) and long-term depression (LTD). The cellular events underlying this important process in learning and memory are still being revealed. Here we describe and characterize the AAA+ ATPase Thorase, which regulates the expression of surface AMPAR. In an ATPase-dependent manner Thorase mediates the internalization of AMPAR by disassembling the AMPAR-GRIP1 complex. Following genetic deletion of Thorase, the internalization of AMPAR is substantially reduced, leading to increased amplitudes of miniature excitatory postsynaptic currents, enhancement of LTP, and elimination of LTD. These molecular events are expressed as deficits in learning and memory in Thorase null mice. Thus, we have identified a novel an AAA+ ATPase that plays a critical role in regulating the surface expression of AMPAR and thereby regulates synaptic plasticity and learning and memory. Abnormal neuronal excitability and impaired synaptic plasticity might occur before the degeneration and death of neurons in Alzheimer's disease (AD). To elucidate potential biophysical alterations underlying aberrant neuronal network activity in AD, we performed whole-cell patch clamp analyses of L-type (nifedipine-sensitive) Ca2+ currents (L-VGCC), 4-aminopyridine-sensitive K+ currents, and AMPA (2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid) and NMDA (N-methyl-D-aspartate) currents in CA1, CA3, and dentate granule neurons in hippocampal slices from young, middle-age, and old 3xTgAD mice and age-matched wild type mice. 3xTgAD mice develop progressive widespread accumulation of amyloid β-peptide, and selective hyperphosphorylated tau pathology in hippocampal CA1 neurons, which are associated with cognitive deficits, but independent of overt neuronal degeneration. An age-related elevation of L-type Ca2+ channel current density occurred in CA1 neurons in 3xTgAD mice, but not in wild type mice, with the magnitude being significantly greater in older 3xTgAD mice. The NMDA current was also significantly elevated in CA1 neurons of old 3xTgAD mice compared with in old wild type mice. There were no differences in the amplitude of K+ or AMPA currents in CA1 neurons of 3xTgAD mice compared with wild type mice at any age. There were no significant differences in Ca2+, K+, AMPA, or NMDA currents in CA3 and dentate neurons from 3xTgAD mice compared with wild type mice at any age. Our results reveal an age-related increase of L-VGCC density in CA1 neurons, but not in CA3 or dentate granule neurons, of 3xTgAD mice. These findings suggest a potential contribution of altered L-VGCC to the selective vulnerability of CA1 neurons to tau pathology in the 3xTgAD mice and to their degeneration in AD patients. Tomosyn, a syntaxin-binding protein, is known to inhibit vesicle priming and synaptic transmission via interference with the formation of SNARE complexes. Using a lentiviral vector, we specifically overexpressed tomosyn1 in hippocampal dentate gyrus neurons in adult mice. Mice were then subjected to spatial learning and memory tasks and electrophysiological measurements from hippocampal slices. Tomosyn1-overexpression significantly impaired hippocampus-dependent spatial memory while tested in the Morris water maze. Further, tomosyn1-overexpressing mice utilize swimming strategies of lesser cognitive ability in the Morris water maze compared with control mice. Electrophysiological measurements at mossy fiber-CA3 synapses revealed impaired paired-pulse facilitation in the mossy fiber of tomosyn1-overexpressing mice. This study provides evidence for novel roles for tomosyn1 in hippocampus-dependent spatial learning and memory, potentially via decreased synaptic transmission in mossy fiber-CA3 synapses. Moreover, it provides new insight regarding the role of the hippocampal dentate gyrus and mossy fiber-CA3 synapses in swimming strategy preference, and in learning and memory. The formation, maintenance and reorganization of synapses are critical for brain development and the responses of neuronal circuits to environmental challenges. Here we describe a novel role for peroxisome proliferator-activated receptor γ co-activator 1α, a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, proliferator-activated receptor γ co-activator 1α overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of proliferator-activated receptor γ co-activator 1α inhibits spinogenesis and synaptogenesis. Proliferator-activated receptor γ co-activator 1α knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor stimulates proliferator-activated receptor γ co-activator-1α-dependent mitochondrial biogenesis by activating extracellular signal-regulated kinases and cyclic AMP response element-binding protein. Proliferator-activated receptor γ co-activator-1α knockdown inhibits brain-derived neurotrophic factor-induced dendritic spine formation without affecting expression and activation of the brain-derived neurotrophic factor receptor tyrosine receptor kinase B. Our findings suggest that proliferator-activated receptor γ co-activator-1α and mitochondrial biogenesis have important roles in the formation and maintenance of hippocampal dendritic spines and synapses.

突触根据环境需求改变其特性的能力（突触可塑性）对于学习和记忆至关重要。 突触可塑性异常与阿尔茨海默病和相关疾病有关。 在我们不断努力了解衰老和神经退行性疾病背景下突触可塑性所涉及的分子机制的过程中，我们取得了几项重大进展。 我们使用正常发育和繁殖但Notch水平降低的Notch反义转基因小鼠来证明Notch信号传导在突触可塑性中的作用。 Notch 水平降低的小鼠表现出海马 CA1 突触的长时程增强 (LTP) 受损。 Notch配体增强正常小鼠的LTP并纠正Notch反义转基因小鼠的LTP缺陷。在Notch水平降低的小鼠中，基础和刺激诱导的NF-κB活性水平显着降低。这些发现表明，Notch 信号传导在与学习和记忆过程相关的突触可塑性形式中发挥着重要作用。 我们发现 Notch1 及其配体 Jagged1 存在于突触处，并且神经元中的 Notch 信号传导响应突触活动而发生。此外，神经元Notch信号传导受到Arc/Arg3.1的正向调节，Arc/Arg3.1是突触可塑性所需的活性诱导基因。在 Arc/Arg3.1 突变神经元中，Notch1 的蛋白水解激活在体内和体外均被破坏。出生后海马体中Notch1的条件性缺失会破坏长时程增强（LTP）和长时程抑制（LTD），并导致学习和短期记忆缺陷。我们的研究结果表明，Notch 信号传导根据神经元活动进行动态调节，Arc/Arg3.1 是上下文依赖性 Notch 调节器，而 Notch1 是有助于记忆形成的突触可塑性所必需的。 AMPA 受体 (AMPAR) 的突触插入或去除在长时程增强 (LTP) 和长时程抑制 (LTD) 表达所反映的突触活性调节中起着关键作用。学习和记忆这一重要过程背后的细胞事件仍在被揭示。在这里，我们描述并表征了 AAA+ ATPase Thorase，它调节表面 AMPAR 的表达。 Thorase 以 ATP 酶依赖性方式通过分解 AMPAR-GRIP1 复合物介导 AMPAR 的内化。 Thorase 基因缺失后，AMPAR 的内化显着减少，导致微型兴奋性突触后电流振幅增加、LTP 增强和 LTD 消除。这些分子事件在 Thorase 缺失小鼠中表现为学习和记忆缺陷。因此，我们发现了一种新型 AAA+ ATP 酶，它在调节 AMPAR 的表面表达中发挥着关键作用，从而调节突触可塑性以及学习和记忆。 阿尔茨海默病（AD）神经元退化和死亡之前可能会出现神经元兴奋性异常和突触可塑性受损。为了阐明 AD 中异常神经元网络活动潜在的生物物理改变，我们对 L 型（硝苯地平敏感）Ca2+ 电流 (L-VGCC)、4-氨基吡啶敏感 K+ 电流和 AMPA 进行了全细胞膜片钳分析 (2 -氨基-3-(3-羟基-5-甲基-异恶唑-4-基)丙酸)和NMDA(N-甲基-D-天冬氨酸)电流年轻、中年和老年 3xTgAD 小鼠和年龄匹配的野生型小鼠海马切片中的 CA1、CA3 和齿状颗粒神经元。 3xTgAD 小鼠在海马 CA1 神经元中出现淀粉样蛋白 β 肽进行性广泛积累和选择性过度磷酸化 tau 病理，这与认知缺陷相关，但与明显的神经元变性无关。 3xTgAD 小鼠的 CA1 神经元中出现了与年龄相关的 L 型 Ca2+ 通道电流密度升高，但野生型小鼠中没有，且老年 3xTgAD 小鼠的幅度明显更大。与老年野生型小鼠相比，老年 3xTgAD 小鼠 CA1 神经元的 NMDA 电流也显着升高。与任何年龄的野生型小鼠相比，3xTgAD 小鼠 CA1 神经元中 K+ 或 AMPA 电流的幅度没有差异。与任何年龄的野生型小鼠相比，3xTgAD 小鼠的 CA3 和齿状神经元中的 Ca2+、K+、AMPA 或 NMDA 电流没有显着差异。我们的结果揭示了 3xTgAD 小鼠 CA1 神经元中 L-VGCC 密度与年龄相关的增加，但 CA3 或齿状颗粒神经元中没有。这些发现表明，改变的 L-VGCC 可能导致 3xTgAD 小鼠 CA1 神经元对 tau 病理学的选择性脆弱性以及 AD 患者的退化。 Tomosyn 是一种突触融合蛋白结合蛋白，已知可通过干扰 SNARE 复合物的形成来抑制囊泡启动和突触传递。使用慢病毒载体，我们在成年小鼠的海马齿状回神经元中特异性过度表达 tomosyn1。然后对小鼠进行空间学习和记忆任务以及海马切片的电生理测量。在 Morris 水迷宫中进行测试时，Tomosyn1 过度表达显着损害海马依赖性空间记忆。此外，与对照小鼠相比，tomosyn1 过表达小鼠在莫里斯水迷宫中使用认知能力较差的游泳策略。对苔藓纤维-CA3 突触的电生理学测量表明，tomosyn1 过表达小鼠的苔藓纤维中的配对脉冲促进受损。这项研究为 tomosyn1 在海马依赖性空间学习和记忆中的新作用提供了证据，可能是通过减少苔藓纤维-CA3 突触中的突触传递来实现的。此外，它还提供了关于海马齿状回和苔藓纤维-CA3突触在游泳策略偏好以及学习和记忆中的作用的新见解。 突触的形成、维持和重组对于大脑发育和神经元回路对环境挑战的反应至关重要。在这里，我们描述了过氧化物酶体增殖物激活受体 γ 共激活剂 1α（线粒体生物发生的主要调节剂）在海马神经元树突棘的形成和维持中的新作用。在培养的海马神经元中，增殖物激活受体 γ 共激活物 1α 过度表达会增加树突棘并增强突触的分子分化，而增殖物激活受体 γ 共激活物 1α 的敲低会抑制树突棘发生和突触发生。增殖剂激活受体 γ 共激活剂 1α 敲低也会降低体内海马齿状颗粒神经元中树突棘的密度。我们进一步表明，脑源性神经营养因子通过激活细胞外信号调节激酶和环AMP反应元件结合蛋白来刺激增殖剂激活受体γ辅激活剂1α依赖性线粒体生物发生。增殖物激活受体γ辅激活剂-1α敲低抑制脑源性神经营养因子诱导的树突棘形成，而不影响脑源性神经营养因子受体酪氨酸受体激酶B的表达和激活。我们的研究结果表明，增殖物激活受体γ辅酶-activator-1α 和线粒体生物发生在海马树突棘和突触的形成和维持中具有重要作用。