Regulation of Synaptic Plasticity in Hippocampus In Vivo

体内海马突触可塑性的调节

• 批准号: 6845727
• 负责人: EDDA THIELS
• 金额: $ 26.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845727
• 关键词: biological signal transduction; cAMP response element binding protein; enzyme activity; enzyme linked immunosorbent assay; gene expression; genetic regulation; hippocampus; immunocytochemistry; in situ hybridization; laboratory rat; long term potentiation; memory; mitogen activated protein kinase; neural plasticity; neuroregulation; neurotransmitter transport; phosphoprotein phosphatase; phosphorylation; protein protein interaction; protein structure function; western blottings

DESCRIPTION (provided by applicant): The neurobiological events that underlie learning and memory likely include activity-dependent modification of synaptic strength in brain structures known to subserve memory. Examples of use-dependent synaptic modification hypothesized to contribute to memory are long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission at excitatory synapses in the hippozampus. Hippocampal LTD, similar to hippocampal LTP, is persistent, lasting for days in area CA1 in vivo. The persistence of LTD suggests that the underlying molecular mechanisms involve altered gene expression, although some of the changes in expression must differ from those involved in LTP. The proposed work addresses this issue by examining the role of the serine/threonine protein phosphatases PP1 and PP2A and that of the extracellular signal-regulated kinase (ERK) cascade in LTD and LTP in area CA1 in vivo. Motivated by previous work from our laboratory and work by others, we propose to pursue the following Specific Aims: (1) To determine whether PP1 or PP2A is responsible for decreased activation of the transcription factor CREB during LTD and plays a role in the persistence of LTD; (2) To determine whether LTD requires de novo transcription and translation and is associated with an increase in ERK/Elk-l-mediated gene expression but not in CREB-mediated expression; and (3) To delineate the role of ERK in the regulation of CREB and Elk-1 function in LTD vs. LTP, and test whether reduced phosphatase action on CREB during LTP contributes to the persistence of LTP. We will address these questions with a combination of in vivo electrophysiological techniques, enzyme activity assays, Western blot and immunohistochemical analyses, and in situ hybridization. Collectively, the studies will elucidate mechanisms of negative and positive regulation of transcriptional signals in response to plasticity-inducing synaptic activation in the adult in vivo hippocampus, and will yield models of how interactions among different signaling events combine in the regulation of bidirectional synaptic plasticity. The findings from these studies will provide the foundation for future work directed at relating signaling events involved in bidirectional synaptic plasticity to signaling events involved in different types of memory operations performed by behaving animals.

描述（由申请人提供）：学习和记忆的基础的神经生物学事件可能包括依赖于活动的突触强度的脑结构中已知可供记忆的突触强度的修饰。假设有助于记忆的使用依赖性突触修饰的例子是Hippozampus兴奋性突触时突触传播的长期增强（LTP）和长期抑郁（LTD）。海马有限公司（Hippocampal Ltd）与海马LTP相似，在体内CA1区域持续数天。 LTD的持久性表明，基本的分子机制涉及基因表达改变，尽管表达的某些变化必须与LTP所涉及的变化不同。提出的工作通过检查丝氨酸/苏氨酸蛋白磷酸酶PP1和PP2A的作用以及在体内Ca1区域Ca1中LTD中的细胞外信号调节激酶（ERK）级联反应的作用。 通过我们实验室的先前工作和其他人的工作，我们建议追求以下特定目标：（1）确定PP1或PP2A是否负责LTD期间转录因子CREB的激活减少，并在LTD持久性中起作用； （2）确定LTD是否需要从头转录和翻译，并且与ERK/ELK-L介导的基因表达的增加相关，但在CREB介导的表达中不存在； （3）描述ERK在LTD中CREB和ELK-1功能的调节中的作用，并测试LTP期间磷酸酶对CREB的降低是否有助于LTP的持久性。我们将通过体内电生理技术，酶活性测定，蛋白质印迹和免疫组织化学分析以及原位杂交的结合来解决这些问题。总的来说，研究将阐明成人体内海马诱导可塑性的突触激活的转录信号负和正调控的机制，并将产生不同信号事件之间相互作用如何结合双向突触可塑性的调节模型。这些研究的发现将为未来的工作提供基础，这些工作致力于将双向突触可塑性涉及的信号事件与与行为动物进行的不同类型的记忆操作有关的信号事件与信号事件。