Role of histone acetyltransferases in memory storage and synaptic plasticity

描述(由申请人提供)： 组蛋白乙酰转移酶在记忆存储和突触可塑性中的作用突触可塑性是大脑中神经元连接强度的变化，被认为是记忆存储的基础，并可能在各种神经和精神疾病中发挥关键作用，包括阿尔茨海默病、智力低下、癫痫和抑郁症。突触可塑性的一种形式是长时程增强(LTP)，这是一种依赖活动的突触增强形式。与长期记忆存储一样，长期形式的LTP在需要蛋白质合成和转录方面不同于短期增强。蛋白激酶A(PKA)与其他激酶一起激活cAMP反应元件结合蛋白(CREB)等转录因子，导致基因诱导和长期记忆储存。然而，基因表达的调控不仅需要CREB等序列特异性转录因子，还需要转录辅助激活因子，如平行因子CREB结合蛋白(CBP)和p300。CBP和p300是有效的组蛋白乙酰转移酶(HATS)，通过改变染色质结构，以细胞类型和启动子特异的方式协调调节基因的活性。许多关于记忆存储和突触可塑性的工作都集中在CBP上。CBP突变和转基因显性阴性小鼠表现出空间学习和海马LTP范型的缺陷。然而，对p300显性阴性转基因小鼠和p300条件性基因敲除的研究也显示了p300在空间记忆中的作用。一种常见的功能丧失的遗传操作还没有被用来研究CBP和p300，以便剖析这些帽子在记忆存储中的需求。该项目旨在使用一种有针对性的方法，通过使用病毒载体，在海马区导致CBP、P300或两者的空间受限删除。这种方法有两个目的：一个是有一个共同的操作来评估副词的不同和重叠的作用，另一个是确定这些因素中的每一个的作用地点是否是海马体。该提案有三个目标：第一，研究这些靶向缺失突变体中的电生理学；特别是研究Schaffer侧枝突触中cAMP、PKA依赖和PKA非依赖的LTP范例。第二个目标是观察这些动物的行为表型，特别是在依赖海马体的任务中，如情景恐惧条件反射和空间物体识别。最后，第三个目标是观察这些突变体在学习范例前后的靶基因表达和这些基因的染色质乙酰化。这些研究将使我们能够比较这两个平行HAT的不同和重叠的靶点，并有助于理解记忆存储过程中神经元中活动依赖的基因激活。 公共卫生相关性： 长期记忆存储和长期形式的突触可塑性涉及基因表达的协调调节，但完成这种转录调节的机制才刚刚开始被理解。我们建议用实验来研究转录共激活因子和组蛋白乙酰化在基因调控中的作用。这些形式的转录调控在基因表达的协调调控中整合了多种信号通路。了解组蛋白乙酰化在记忆存储和突触可塑性中的作用，最终可能会导致开发治疗精神分裂症、神经退行性疾病、智能障碍和抑郁症等疾病的新疗法。

DESCRIPTION (provided by applicant): The role of histone acetyltransferases in memory storage and synaptic plasticity Synaptic plasticity, the change in the strength of neuronal connections in the brain, is thought to underlie memory storage and may play a crucial role in a variety of neurological and mental disorders, including Alzheimer's disease, mental retardation, epilepsy and depression. One form of synaptic plasticity that has received much attention is long-term potentiation (LTP), an activity-dependent form of synaptic enhancement. Like long-term memory storage, long-lasting forms of LTP differ from short-term potentiation in requiring protein synthesis, and transcription. Protein kinase A (PKA) acts along with other kinases to activate transcription factors such as cAMP response element binding protein (CREB), leading to gene induction and long-term memory storage. The regulation of gene expression, however, requires not only sequence-specific transcription factors like CREB, but also transcriptional coactivators, such as the paralogous factors CREB- binding protein (CBP) and p300. CBP and p300 are potent histone acetyltransferases (HATs) that coordinately regulate gene activity in a cell type- and promoter-specific fashion by modifying chromatin structure. Much of the work in memory storage and synaptic plasticity has been focused on CBP. CBP mutant and transgenic dominant negative mice show deficits in spatial learning, and in hippocampal LTP paradigms. However, work on p300 dominant negative transgenic mice and p300 conditional knockouts also show a role for p300 in spatial memory. A common loss-of-function genetic manipulation has not been used to study both CBP and p300, in order to dissect the requirement of these HATs in memory storage. This project aims to use a targeted approach that would result in a spatially restricted deletion of CBP, p300 or both in the hippocampus, through the use of a viral vector. This approach serves two purposes: one is to have a common manipulation to assess the different and overlapping roles of the paralogues, and the other is to determine if the locus of action of each of these factors is the hippocampus. The proposal has three aims: the first is to look at the electrophysiology in these targeted deletion mutants; specifically looking at cAMP-, and PKA-dependent, and PKA-independent LTP paradigms in the Schaffer collateral synapse. The second aim is to look at the behavioral phenotypes of these animals, especially in hippocampus-dependent tasks such as contextual fear conditioning, and spatial object recognition. Finally, the third aim is to look at target gene expression and chromatin acetylation of these genes in these mutants, before and after a learning paradigm. These studies would allow us to compare the different and overlapping targets of these two paralogous HATs, and help in the understanding of activity-dependent gene activation in the neuron during memory storage. PUBLIC HEALTH RELEVANCE: Long-term memory storage and long-lasting forms of synaptic plasticity involve the coordinate regulation of gene expression, but the mechanisms by which this transcriptional regulation is accomplished are only beginning to be understood. We propose experiments to examine the role of transcriptional co-activators and histone acetylation in gene regulation. These forms of transcriptional regulation integrate multiple signaling pathways in the coordinated regulation of gene expression. Understanding the role of histone acetylation in memory storage and synaptic plasticity may ultimately lead to the development of new treatments for disorders such as schizophrenia, neurodegenerative diseases, intellectual disability and depression.