Molecular Mechanisms of Synapse Development and Plasticity

突触发育和可塑性的分子机制

• 批准号: 10011367
• 负责人: Zheng Li
• 金额: $ 109.79万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 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/10011367
• 关键词: AMPA Receptors; Adolescence; Adverse event; Anxiety Disorders; Autophagocytosis; Autopsy; Behavior; Behavioral; Binding Proteins; Biogenesis; Brain; Brain Diseases; Caspase; Cell physiology; Cognitive; Coiled-Coil Domain; Complex; Dendritic Spines; Development; Dopamine; Dystrophin; Electrophysiology (science); Emotional; Endocytosis; Excitatory Synapse; FRAP1 gene; Filopodia; Goals; Growth; Individual; Information Storage; Knockout Mice; Long-Term Depression; Long-Term Potentiation; Lysosomes; Mammalian Cell; Mediator of activation protein; Mental Depression; Mental disorders; Messenger RNA; Molecular; Mus; Mutant Strains Mice; Neurons; Neurotransmitters; Organelles; Pathology; Pharmacology; Physiology; Preventive; Process; Proteins; Reporting; Role; Schizophrenia; Signal Pathway; Site; Slice; Social Behavior; Stress; Structure; Subcellular structure; Synapses; Synaptic Transmission; Synaptic plasticity; Therapeutic; Thinness; Wild Type Mouse; Work; autism spectrum disorder; experience; inhibitor/antagonist; insight; mTOR Inhibitor; mutant; neural circuit; postsynaptic; postsynaptic neurons; presynaptic; presynaptic neurons; receptor; receptor internalization; stem; synaptic function; trafficking

1. The molecular mechanism underlying long-term synaptic depression. The strength of synaptic transmission can change through synaptic plasticity. Long-lasting forms of synaptic plasticity (such as long-term potentiation and long-term depression of synaptic transmission) are important cellular mechanisms underlying information storage in the brain and the establishment of proper neural circuits during development. In this project, we investigate the mechanism underlying the induction of long-term depression of synaptic transmission (LTD). Our group previously reported that caspases are activated during LTD to induce AMPA receptor internalization. During the past few years, we have been investigating the mechanism by which caspases regulated AMPA receptor trafficking, We found that macroautophagy(autophagy hereinafter) is a mediator of caspases in LTD. Autophagy is a cellular process for the degradation of cytoplasmic components and organelles via lysosomes. Autophagy is also essential for the development and function of synapses. It enables the developmental pruning of dendritic spines (subcellular structures accommodating postsynaptic components), and regulates presynaptic structure, dopamine release, and degradation of postsynaptic receptors. Anomalous autophagy is associated with brain disorders. Autophagy is orchestrated by more than 30 autophagy-related (Atg) proteins and multiple signaling pathways. Mechanistic target of rapamycin complex 1 (mTORC1) is the best-characterized autophagy regulator in mammalian cells. Using mTOR inhibitors and knockout mice with deficient autophagy, we found that autophagic flux changes during LTD and this in turn leads to AMPA receptor endocytosis. During this reporting period, we investigated how autophagy interacts with the endosomal trafficking of AMPA receptors and the influence of autophagy on the behavior of mice. 2. The role of dysbindin-1 in synaptic physiology. Dysbindin-1 is a coiled-coil domain containing protein, initially discovered as a dystrophin-binding protein and later found to be one of eight subunits of biogenesis of lysosome-related organelles complex 1 (BLOC-1). The postmortem brains of individuals with schizophrenia have reduced dysbindin-1 proteins and mRNAs. Our earlier work shows that dysbindin-1 contributes to the establishment of neuronal connectivity during adolescence by regulating the growth of dendritic protrusions, including dendritic spines (tiny dendritic protrusions where excitatory synapses are formed) and filopodia (long, thin protrusions that are precursors of dendritic spines in young neurons). During this review period, we investigated the role of dysbindin-1 in psychogenic stress-induced synaptic alterations. We conducted electrophysiological recordings in brain slices taken from dysbindin-1 mutant and wild-type mice. We found that after mild psychogenic stress, synaptic plasticity can be more easily induced in dysbindin-1 mutant mice than in wild-type mice. Because of this reduced synaptic plasticity threshold, the social behavior of dysbindin-1 mutant mice is altered by mild stress that has no significant effect on wild-type mice. We applied pharmacological inhibitors of various neurotransmitters to examine the mechanism underlying this phenomenon.

1.长时程突触抑制的分子机制。突触传递的强度可以通过突触可塑性而改变。突触可塑性的持久形式（如突触传递的长时程增强和长时程抑制）是大脑中信息储存和发育过程中正确神经回路建立的重要细胞机制。在这个项目中，我们研究了突触传递（LTD）的长时程抑制的诱导机制。我们的小组以前报道过，半胱天冬酶在LTD过程中被激活，诱导AMPA受体内化。在过去的几年中，我们一直在研究caspase调控AMPA受体运输的机制，发现巨自噬（macroautophagy，以下简称自噬）是LTD中caspase的介导物。自噬是通过溶酶体降解细胞质成分和细胞器的细胞过程。自噬对于突触的发育和功能也是必不可少的。它使树突棘（容纳突触后成分的亚细胞结构）的发育修剪，并调节突触前结构，多巴胺释放和突触后受体的降解。异常的自噬与大脑疾病有关。 自噬由30多种自噬相关蛋白和多种信号通路协调。雷帕霉素复合物1（mTORC 1）的机制靶标是哺乳动物细胞中最具特征的自噬调节剂。使用mTOR抑制剂和自噬缺陷的敲除小鼠，我们发现LTD期间自噬通量发生变化，这反过来导致AMPA受体内吞作用。在本报告期间，我们研究了自噬如何与AMPA受体的内体运输相互作用以及自噬对小鼠行为的影响。 2. dysbindin-1在突触生理学中的作用。Dysbindin-1是一种含有卷曲螺旋结构域的蛋白质，最初被发现为抗肌萎缩蛋白结合蛋白，后来被发现是溶酶体相关细胞器复合物1（BLOC-1）生物发生的八个亚基之一。精神分裂症患者的死后大脑具有减少的dysbindin-1蛋白和mRNA。我们早期的工作表明，dysbindin-1通过调节树突突起的生长，包括树突棘（形成兴奋性突触的微小树突突起）和丝状伪足（年轻神经元中树突棘的前体长而细的突起），有助于青春期神经元连接的建立。 在此审查期间，我们调查了dysbindin-1在心因性应激诱导的突触改变中的作用。我们在取自dysbindin-1突变型和野生型小鼠的脑切片中进行了电生理记录。我们发现，在轻度心因性应激后，dysbindin-1突变小鼠比野生型小鼠更容易诱导突触可塑性。由于这种降低的突触可塑性阈值，dysbindin-1突变小鼠的社会行为被轻度应激改变，而对野生型小鼠没有显著影响。我们应用各种神经递质的药理学抑制剂来研究这种现象背后的机制。