Regulation of Synaptic Plasticity in Hippocampus In Vivo

描述（由申请人提供）：作为学习和记忆基础的神经生物学事件可能包括在已知的服务于记忆的大脑结构中突触强度的活动依赖性修改。假设使用依赖性突触修饰有助于记忆的例子是海马兴奋性突触突触传递的长期增强（LTP）和长期抑制（LTD）。海马LTD与海马LTP相似，在体内CA1区具有持续性，可持续数天。LTD的持续存在表明潜在的分子机制涉及基因表达的改变，尽管一些表达的变化必须与LTP所涉及的变化不同。本研究通过研究丝氨酸/苏氨酸蛋白磷酸酶PP1和PP2A以及细胞外信号调节激酶（ERK）级联在CA1区LTD和LTP中的作用来解决这一问题。

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.