即刻早基因Arc参与调控突触后致密区蛋白质相互作用并弱化突触功能的相分离机制研究

突触可塑性，即突触强度的改变，包括长时程增强和长时程减弱等，被认为是学习记忆的重要分子细胞机制。作为一种复杂的信号传导，众多分子都在其中扮演着重要的角色，通过在时间空间上精细地互相协调来实现。其中，即刻早基因ARC就是一个调控突触强度的关键分子，然而相关的分子机制尚不明确。领域内早期认为Arc蛋白和胞吞分子机器互作来介导AMPA受体的内吞，从而削弱突触的电信号传递能力。考虑到突触后致密区（PSD）极其致密的特点，这个模型是否正确尚具争议。在我们的研究中，我们通过体外生化重构PSD的相分离系统惊喜地发现Arc蛋白可以直接将AMPA受体亚基Stargazin（Stg）从PSD凝聚体解离出去，而蛋白质生物化学研究揭示这一现象是由直接的蛋白-蛋白相互作用来实现的。我们和合作者继而在体外培养神经元系统用荧光成像方法验证了这一假说，并且阐明了AMPA受体不同的亚基对Arc介导的解离敏感度是不同的，这说明AMPA受体不同亚基的脑区分布会影响该脑区的突触对Arc的响应能力。此外，AMPA受体亚基的磷酸化修饰也会让其对Arc不敏感，结合领域内的现有模型，我们认为这是一种重要的保护活化突触的机制。因此，我们的研究指出Arc通过直接调控PSD蛋白网络的相分离来直接调控突触的强度，即突触可塑性，且该过程受到多重调控，来更好地协调神经网络范围内的突触可塑性。该数据集共包括六个文件夹、六个表格和一个PDF文件，共130MBSynaptic plasticity, defined as alterations in synaptic strength including long-term potentiation (LTP) and long-term depression (LTD), is widely recognized as a critical molecular and cellular mechanism underlying learning and memory. As a complex signaling process, it relies on the precise spatiotemporal coordination of numerous molecular players. Among these, the immediate early gene ARC has been identified as a key regulator of synaptic strength, yet its underlying molecular mechanisms remain largely unclear. Early studies in the field proposed that Arc protein interacts with the endocytic molecular machinery to mediate endocytosis of AMPA receptors, thereby impairing synaptic electrical transmission. However, given the extremely dense nature of the postsynaptic density (PSD), the validity of this model has been a subject of debate. In our study, by in vitro biochemical reconstitution of a PSD phase separation system, we unexpectedly discovered that Arc protein can directly dissociate the AMPA receptor subunit Stargazin (Stg) from PSD condensates. Subsequent protein biochemistry experiments revealed that this phenomenon is mediated by direct protein-protein interactions. We and our collaborators further validated this hypothesis in primary cultured neuronal systems using fluorescence imaging, and elucidated that distinct AMPA receptor subunits exhibit different sensitivities to Arc-mediated dissociation. This finding indicates that the regional distribution of AMPA receptor subunits in the brain influences the responsiveness of synapses in that brain region to Arc regulation. Additionally, phosphorylation modifications of AMPA receptor subunits render them insensitive to Arc, which, when combined with existing models in the field, suggests this represents an important mechanism that protects activated synapses. Thus, our study demonstrates that Arc directly regulates synaptic strength (i.e., synaptic plasticity) by modulating the phase separation of the PSD protein network, and this process is subject to multiple layers of regulation to better coordinate synaptic plasticity across neural circuits. This dataset consists of six folders, six tables, and one PDF file, with a total size of 130 MB.

搜集汇总

背景与挑战

背景概述

该数据集聚焦于即刻早基因Arc如何通过调控突触后致密区的相分离机制，介导AMPA受体从PSD解离，从而弱化突触功能。研究揭示了Arc直接参与蛋白质相互作用，影响突触可塑性，数据集包含多个文件，总容量为130MB。