Molecular Mechanisms of Synapse Development and Plasticity

1. 长期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而改变。突触可塑性的长期形式（如突触传递的长期增强和长期抑制）是大脑信息储存和发育过程中适当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）长期抑制的机制。我们的研究小组之前报道过，在LTD期间，半胱天冬酶被激活以诱导AMPA受体内化。在过去的几年中，我们一直在研究caspase调节AMPA受体转运的机制，我们发现巨噬（以下简称自噬）是LTD中caspase的中介。自噬是细胞质成分和细胞器通过溶酶体降解的细胞过程。自噬对突触的发育和功能也是必不可少的。它使树突棘（适应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。异常自噬与脑部疾病有关。

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.