Molecular mechanisms underlying the choice between homeostasis and activity-dependent plasticity at the synapse

从苍蝇到人类，突触都是由促进或限制突触变化的塑料事件塑造的 力量。事实上，神经元活动的变化可以导致突触性质/强度的改变。 这种能力被称为活动依赖性突触可塑性(ADSP)。另一种形式的可塑性，称为 突触动态平衡，旨在维持突触的输出以确保稳定的活动。这两个截然不同的 突触可塑性的形式是认知过程的中心。事实上，ADSP被认为是细胞 学习和记忆相关，而SH的紊乱与一系列神经疾病有关。至 到目前为止，大多数研究都将这两种形式的可塑性分开考虑。问题仍然是：一个 Synapse将两者整合在一起，以确保其输出的稳定性，同时仍允许突触的离散变化 在需要的时候需要力量吗？在这里，我们建议在单个突触水平上研究 ADSP和SH。此外，我们将突出显示两个相互排斥的相互对立的分子控制器 在这两种可塑性模式之间做出选择。 利用果蝇神经肌肉接头(NMJ)，我们建议证明转录因子 醋栗(GSB，Pax3/7同源物)和信号分子无翼(WG，WNT同源物) 决定突触可塑性的拮抗功能。利用遗传学、免疫组织化学和 电生理学，我们首先要问的是，诱发SH是否扰乱了随后的ADSP，反之亦然。这将允许 我们要描述这两种形式的可塑性的相互排他性，并知道其中一种形式是否会取代 另一个或是否他们参与的顺序是决定因素。然后我们将展示一个 SH、GSB必需基因抑制ADSP。同样，我们会问，支持ADSP的信号是否 WG对SH有拮抗作用。最后，我们将描述GSB和WG之间的遗传交互作用，以支持这一想法 这两个分子之间的对立。 这项工作将确定是否存在一个等级或临时组织来确定 主要的可塑性。这也将有助于理解这一现象背后的一个分子系统 组织。这将对我们理解ADSP和SH的整合做出重大贡献。此外， 这将使我们处于一个理想的位置来剖析Wg指导的突触靶点的功能和调节 和GSB在这些可塑性过程中。

From flies to humans, synapses are shaped by plastic events that promote or limit changes in synaptic strength. Indeed, changes in neuronal activity can lead to modifications in the property/strength of the synapse. This ability is called activity-dependent synaptic plasticity (ADSP). Another form of plasticity, referred to as synaptic homeostasis (SH), aims at maintaining synaptic output to ensure stable activity. These two distinct forms of synaptic plasticity are at the center of processes of cognition. Indeed, ADSP is regarded as the cellular correlate of learning and memory while perturbations of SH are linked to an array of neurological diseases. To date, most studies have considered these two forms of plasticity separately. The question remains: how does a synapse integrate the two to ensure the stability of its output while still allowing for discrete changes in synaptic strength when required? Here we propose to study, at a single synapse level, the apparent antagonism between ADSP and SH. In addition, we will highlight two opposing molecular controllers underlying the mutually exclusive choice between these two modes of plasticity. Using the Drosophila Neuromuscular junction (NMJ), we propose to show that the transcription factor gooseberry (gsb, the pax3/7 homolog) and the signaling molecule wingless (wg, the wnt homolog) have antagonistic functions which determine synaptic plasticity. Using genetics, immunohistochemistry and electrophysiology, we will first ask whether eliciting SH perturbs subsequent ADSP and vice versa. This will allow us to characterize the mutual exclusivity of the two forms of plasticity and know whether one form supersedes the other or whether the order in which they are engaged is the determining factor. We will then show that a gene characterized as essential to SH, gsb, inhibits ADSP. Similarly, we will ask whether the pro-ADSP signal Wg antagonizes SH. Finally, we will characterize genetic interactions between gsb and wg supporting the idea of antagonism between the two molecules. This work will determine whether there is a hierarchical or temporal organization that determines the predominant plasticity. It will also contribute to understanding one of the molecular systems underlying this organization. It will be a major contribution to our understanding of the integration of ADSP and SH. Furthermore, it will place us in an ideal position to dissect the function and regulation of the synaptic targets directed by Wg and Gsb during these processes of plasticity.