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（突触可塑性）改变其性质的能力对于学习和记忆至关重要。 突触可塑性异常与阿尔茨海默氏病和相关疾病有关。 在我们继续努力理解突触可塑性涉及的分子机制的过程中，在衰老和神经退行性疾病的背景下，我们取得了一些重大进步。 我们使用了正常发展和再现的Notch反义转基因小鼠，但表现出降低的水平，以证明缺口信号在突触可塑性中的作用。水位降低的小鼠在海马CA1突触上表现出长期增强（LTP）的受损。 Notch配体可以增强正常小鼠的LTP，并纠正Notch反义转基因小鼠LTP中的缺陷。在缺口水平降低的小鼠中，基底和刺激诱导的NF-kappa B活性显着降低。这些发现表明，Notch信号传导的重要作用以一种已知与学习和记忆过程相关的突触可塑性形式。 我们发现Notch1及其配体Jagged1存在于突触中，并且神经元中的Notch信号转导响应突触活动。此外，神经元凹槽信号传导由ARC/ARG3.1阳性调节，Arc/arg3.1是突触可塑性所需的活性诱导的基因。在ARC/ARG3.1突变神经元中，Notch1的蛋白水解活化在体内和体外都受到破坏。产后海马中Notch1的条件缺失破坏了长期增强（LTP）和长期抑郁症（LTD），并导致学习和短期记忆缺陷。我们的发现表明，Notch信号是根据神经元活性动态调节的，ARC/ARG3.1是一种依赖上下文的Notch调节器，而Notch1对于有助于记忆形成的突触可塑性是必需的。 AMPA受体（AMPAR）的突触插入或去除在调节长期增强表达（LTP）和长期抑郁（LTD）中的突触活性中起关键作用。学习和记忆中这一重要过程的基础事件仍在揭示。在这里，我们描述并表征AAA+ ATPase Thrase，该the酶调节表面AMPAR的表达。以ATPase依赖性方式，Thorase通过拆卸AMPAR-GRIP1复合物来介导AMPAR的内在化。遗传缺失的胸酶缺失后，AMPAR的内在化大大降低，导致微型兴奋性突触后电流的幅度增加，LTP的增强和消除LTD的幅度。这些分子事件表示为在胸酶null小鼠中学习和记忆中的缺陷。因此，我们已经确定了一种新颖的AAA+ ATPase，该AAA+ ATPase在调节AMPAR的表面表达中起着至关重要的作用，从而调节突触可塑性，学习和记忆。 神经元的兴奋性异常和突触可塑性受损可能发生在阿尔茨海默氏病（AD）中神经元的变性和死亡之前。为了阐明AD中异常神经元网络活性的潜在生物物理改变，我们对L型（Nifedipine敏感）Ca2+电流（L-VGGCC），4-氨氨基吡啶敏感的K+ Cournent和AMPA进行了L型（Nifedipine敏感的）Ca2+电流（L-VGGCC）的全细胞贴片夹分析（2-氨基-3-（3-羟基-5-甲基 - 异恶唑-4-基）丙酸）和NMDA（NMDA（N-甲基-D-天冬氨酸）电流中的Ca1，Ca3和齿状颗粒神经元中的齿状颗粒神经元，来自年轻，中等年龄，中等年龄和旧的3xt-axt-Age和Old 3xtgad鼠标和年龄较大的鼠标型和年龄pypece。 3XTGAD小鼠在海马CA1神经元中淀粉样蛋白β肽的逐渐广泛积累，以及与认知缺陷相关的选择性高磷酸化taU病理学，但与明显的神经元变性有关。在3xTGAD小鼠的CA1神经元中，L型Ca2+通道电流密度与年龄相关的升高，但在野生型小鼠中不存在，其中3xtgad小鼠的幅度明显更大。与旧野生型小鼠相比，在旧3xtgad小鼠的CA1神经元中，NMDA电流也显着升高。与任何年龄的野生型小鼠相比，3xtgad小鼠的Ca1神经元中K+或AMPA电流的振幅没有差异。与任何年龄段的野生型小鼠相比，CA3中的Ca2+，K+，AMPA或NMDA电流没有显着差异。我们的结果表明，CA1神经元中L-VGCC密度的年龄相关，但在3xtgad小鼠的Ca3或齿状颗粒神经元中不增加。这些发现表明，L-VGCC改变对3XTGAD小鼠中CA1神经元对Tau病理学的选择性脆弱性以及AD患者的退化有潜在的贡献。 tomosyn是一种语法结合蛋白，已知可以通过干扰SNARE复合物的形成来抑制囊泡启动和突触传播。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别表达了tomosyn1。然后，将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。在莫里斯水迷宫中测试的同时，tomosyn1的过表达显着损害了海马依赖性空间记忆。此外，与对照小鼠相比，莫里斯水迷宫中较低的认知能力的游泳策略利用了较低的认知能力的游泳策略。苔藓纤维-CA3突触的电生理测量结果揭示了在tomosyn1过表达的小鼠的苔藓纤维中成对的脉冲促进性受损。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，这可能是通过苔藓纤维-CA3突触中的突触传播减少的。此外，它提供了有关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，维护和重组对于大脑发育以及神经元电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的受体γ共激活剂1α，即线粒体生物发生的主要调节剂，在海马神经元中树突状棘的形成和维持中。在培养的海马神经元中，增生剂激活的受体γ共激活剂1α过表达增加了树突状刺并增强了突触的分子分化，而敲除增殖器激活的受体γ共驱动器γ共驱动器1α抑制了抑制微分发生和突发发生。增殖物激活的受体γ共激活剂1α敲低还降低了体内海马齿状颗粒神经元中树突状棘的密度。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状AMP反应元件结合蛋白来刺激增生剂激活的受体γ共激活剂1α依赖性线粒体生物发生。增生剂激活受体γ共激活器1α敲低抑制脑源性神经营养因子诱导的树突状脊柱形成而不影响脑源性神经营养因子受体受体受体激酶的表达和激活。海马树突状刺和突触的形成和维护。