Molecular Mechanisms of Synapse Development and Plasticity

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的可塑性来改变。长时间的突触可塑性(如突触传递的长期增强和长期抑制)是大脑中信息存储和发育过程中建立适当神经回路的重要细胞机制。在这个项目中，我们研究了诱导长期突触传递抑制(LTD)的机制。本课题组曾报道，半胱氨酸天冬氨酸氨基转移酶在LTD期间被激活以诱导AMPA受体内化。在过去的几年里，我们一直在研究caspase调节AMPA受体转运的机制，我们发现巨大的自噬(以下简称自噬)是caspase在LTD中的中介。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)的发育修剪成为可能，并调节突触前结构、多巴胺释放和突触后受体的降解。异常的自噬与大脑紊乱有关。 自噬是由30多种自噬相关(ATG)蛋白和多条信号通路调控的。雷帕霉素复合体的机械靶点1(MTORC1)是哺乳动物细胞中最具特性的自噬调节因子。使用mTOR抑制剂和自噬缺陷的基因敲除小鼠，我们发现自噬通量在LTD期间发生变化，这反过来导致AMPA受体内吞。在本报告期间，我们调查了自噬如何与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.异常结合蛋白-1在突触生理学中的作用。Dybindin-1是一个含有卷曲结构域的蛋白质，最初被发现是一种抗肌营养不良蛋白结合蛋白，后来被发现是溶酶体相关细胞器复合体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减少了dybindin-1蛋白和mRNAs。我们早期的工作表明，dybindin-1通过调节树突起的生长而促进青春期神经元连通性的建立，包括树突棘(形成兴奋性突触的微小树突起)和丝状足突(年轻神经元中树突棘的前体)。 在此综述期间，我们研究了异常结合蛋白-1在心理应激诱导的突触改变中的作用。我们进行了脑片的电生理记录，这些脑片取自基因突变和野生型小鼠的脑片。我们发现，在温和的心理应激之后，与野生型小鼠相比，异常结合蛋白-1突变小鼠更容易诱导突触可塑性。由于突触可塑性阈值降低，轻度应激改变了异常结合蛋白-1突变小鼠的社会行为，对野生型小鼠没有显著影响。我们应用了各种神经递质的药物抑制剂来研究这种现象的机制。

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.