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

突触稳态和活动依赖性可塑性之间选择的分子机制

• 批准号: 10020797
• 负责人: Bruno Marie
• 金额: $ 18.69万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020797
• 关键词: Affect; Appearance; Black Currant; Chemosensitization; Cognition; Data; Dissection; Drosophila genus; Electrophysiology (science); Ensure; Event; Financial compensation; Frequencies; Genes; Genetic; Homeostasis; Homologous Gene; Human; Immunohistochemistry; Knowledge; Lead; Learning; Link; Maintenance; Measures; Memory; Modification; Molecular; Motor Neurons; Nervous system structure; Neuromuscular Junction; Neuronal Plasticity; Neurons; Orthologous Gene; Output; Pathway interactions; Play; Positioning Attribute; Preparation; Process; Property; Reagent; Regulation; Role; Seizures; Shapes; Signal Transduction; Signaling Molecule; Stimulus; Structure; Synapses; Synaptic plasticity; System; Testing; Work; fly; genetic strain; inhibitor/antagonist; mutant; nervous system disorder; overexpression; quantum; transcription factor

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.

从苍蝇到人类，突触是由可塑性事件塑造的，这些可塑性事件促进或限制了突触的变化。 实力事实上，神经元活动的变化可以导致突触的性质/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 突触稳态（synaptic homeostasis，SH），旨在维持突触输出以确保稳定的活动。这两个不同 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 SH与学习和记忆相关，而SH的扰动与一系列神经系统疾病有关。到 迄今为止，大多数研究分别考虑了这两种形式的可塑性。问题仍然是：一个 突触将这两者结合起来，以确保其输出的稳定性，同时仍然允许突触中的离散变化。 需要时的强度？在这里，我们建议在单个突触水平上研究， ADSP和SH。此外，我们将强调两个相互排斥的分子控制器 在这两种可塑性模式之间进行选择。 使用果蝇神经肌肉接头（NMJ），我们建议表明，转录因子 醋栗（gsb，pax 3/7同系物）和信号分子wingless（wg，wnt同系物）具有 决定突触可塑性的拮抗功能。利用遗传学，免疫组织化学和 在电生理学中，我们将首先询问引发SH是否扰乱随后的ADSP，反之亦然。这将允许 我们的特点是相互排斥的两种形式的可塑性，并知道是否有一种形式取代 另一个或他们参与的顺序是否是决定因素。我们将证明， 作为SH所必需的基因，gsb抑制ADSP。同样，我们会问，支持ADSP的信号 Wg拮抗SH。最后，我们将描述支持这一想法的gsb和wg之间的遗传相互作用 两种分子之间的拮抗作用。 这项工作将确定是否有一个层次或时间组织，决定了 可塑性强。它也将有助于理解其中一个分子系统的基础， organization.这将对我们理解ADSP和SH的集成做出重大贡献。此外，委员会认为， 它将使我们处于一个理想的位置，以剖析由Wg指导的突触靶点的功能和调节。 和Gsb在这些可塑性的过程中。