SSA - The Molecular Mechanisms of Experience-Dependent Synaptic Plasticity at both the Cellular and Behavioural Level.

SSA - 细胞和行为水平上经验依赖性突触可塑性的分子机制。

• 批准号: 1643072
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1643072
• 关键词: SSA; Molecular; Mechanisms; Experience; Dependent

Learning and memory are fundamental processes that define an individual's identity, thoughts and personality. This project aims to characterise and understand fundamental molecular mechanisms of learning and memory mediated by the CREB activating kinase MSK1, providing insight into the molecular changes underlying synaptic plasticity. Greater activation of the synapse, and thus CREB phosphorylation up-regulates CREB-mediated gene transcription, eventually strengthening the synapse, and this change is associated with long-term memory formation.Over the course of this project, correlates of long-term memory formation will be looked at, such as neuron morphology, dendrite spine density and branching, the ion conductance properties of neurons, the localisation of proteins within the post-synaptic membrane, glutamate receptor subunit composition, RNA-sequencing data and spatial memory based behavioural assays in order to elucidate the molecular differences between the MSK1 kinase-dead (KD) mutant and the wildtype (WT) genotype brought about when each is raised in an enriched environment (a housing environment that has been previously observed to increase hippocampal spine density, and aid in spatial learning). Any differences detected would offer an insight into the molecular changes induced by MSK1 during memory formation.Previously generated MSK1 KD mice will be used, that are homozygous for a single point mutation in the MSK1 gene, disrupting the kinase activity of MSK1 specifically. Observations with the KD mutant mice indicate impaired spatial learning and a lack of response to environmental enrichment (less dense hippocampal dendritic trees) as compared to WT mice, indicating that the benefits of environmental enrichment are mediated at least in part by MSK1 kinase activity.Observation of differences in synaptic transmission and properties across genotypes and housing conditions will give an insight into the molecular mechanisms of learning and memory.

学习和记忆是定义个人身份、思想和个性的基本过程。该项目旨在研究和理解CREB激活激酶MSK 1介导的学习和记忆的基本分子机制，从而深入了解突触可塑性的分子变化。突触的更大激活，因此CREB磷酸化上调CREB介导的基因转录，最终加强突触，这种变化与长期记忆的形成有关。在这个项目的过程中，将研究长期记忆形成的相关因素，如神经元形态，树突棘密度和分支，神经元的离子电导特性，突触后膜内蛋白质的定位，谷氨酸受体亚单位的组成，RNA测序数据和基于空间记忆的行为测定，以阐明当各自在富集环境中饲养时，MSK1激酶死亡（KD）突变体和野生型（WT）基因型之间的分子差异（先前已经观察到的增加海马棘密度并有助于空间学习的居住环境）。检测到的任何差异都将提供对记忆形成过程中由MSK 1诱导的分子变化的深入了解。将使用先前产生的MSK 1 KD小鼠，其对于MSK 1基因中的单点突变是纯合的，特异性地破坏MSK 1的激酶活性。对KD突变小鼠的观察表明，它们的空间学习能力受损，对丰富的环境缺乏反应（较不密集的海马树突树），这表明环境丰富的益处至少部分是由MSK 1激酶活性介导的。观察不同基因型和饲养条件下突触传递和特性的差异将有助于深入了解学习的分子机制和记忆

项目成果

The Kinase Function of MSK1 Regulates BDNF Signaling to CREB and Basal Synaptic Transmission, But Is Not Required for Hippocampal Long-Term Potentiation or Spatial Memory.

• DOI: 10.1523/eneuro.0212-16.2017
• 发表时间: 2017-01
• 期刊: eNeuro
• 影响因子: 3.4
• 作者: Daumas S;Hunter CJ;Mistry RB;Morè L;Privitera L;Cooper DD;Reyskens KM;Flynn HT;Morris RG;Arthur JS;Frenguelli BG
• 通讯作者: Frenguelli BG