Mechanisms of plasticity at the Mossy Fiber Synapse

苔藓纤维突触的可塑性机制

• 批准号: 7220606
• 负责人: Anis Contractor
• 金额: $ 28.85万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7220606
• 关键词: Actins; Animals; Anus; Architecture; Brain; Buffers; Calcium; Chromosome Pairing; Classification; Computer information processing; Consensus; Contractor; Cytoskeleton; Data; Disruption; Eph Family Receptors; EphA1 Receptor; Ephrin B Receptor; Ephrin-B3; Ephrins; Excitatory Synapse; F-Actin; Family member; Heterogeneity; Hippocampus (Brain); Impairment; In Vitro; Investigation; LacZ Genes; Learning; Leukotriene E; Ligands; Link; Long-Term Potentiation; Measures; Mediating; Membrane; Memory; Methods; Modeling; Modification; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; N-Methyl-D-Aspartate Receptors; Nerve; Neuraxis; Neurons; PDZ protein; Pathology; Pathway interactions; Peptides; Perfusion; Plastics; Play; Presynaptic Terminals; Probability; Process; Property; Proteins; Protocols documentation; Pyramidal Cells; Rage; Range; Rate; Recurrence; Reporting; Research Personnel; Resolution; Retrieval; Role; Signal Transduction; Signaling Protein; Site; Structure; Synapses; Synaptic Transmission; Synaptic Vesicles; Synaptic plasticity; Testing; Training; dentate gyrus; hippocampal pyramidal neuron; inhibitor/antagonist; insight; interest; memory process; mossy fiber; mutant; nervous system disorder; neurotransmitter release; novel; polymerization; postnatal; postsynaptic; presynaptic; programs; protein protein interaction; receptor; research study; synaptic function; transmission process

DESCRIPTION (provided by applicant): Activity driven modification of excitatory synapses is an exquisitely powerful process for the refinement of synaptic connections. Long-term potentiation (LTP) of synaptic transmission in the hippocampus is widely accepted to be integral to the formation and consolidation of memories. Due to the complexity and heterogeneity of the molecules underlying LTP, many of the cellular mechanisms are still not fully established. A complete description of these fundamental processes will allow us to understand the pathology of neurological disorders that result in the disruption of memory storage and retrieval. The mossy fiber synapse provides one of the main excitatory inputs to the CA3 region of the hippocampus. The recurrent network of the CA3 is particularly important in the storage and retrieval of associative memories. The mossy fiber synapse is critical to the modulation of this network and therefore is central to hippocampal function. Mossy fiber plasticity demonstrates some very interesting properties. LTP is expressed in the presynaptic terminal of the synapse, however there is still controversy over the site of induction. Recent findings have demonstrated a role for postsynaptic mechanism in the induction of mossy fiber LTP followed by trans-synaptic signaling to the pre-synapse, mediated by Eph receptor-ephrin interactions. In order to further explore the molecules involved in this unique pathway, this study will make use of mutant mice in which the relevant proteins have been genetically ablated or mutated to disrupt their signaling function. In addition, we will explore the exact pre- and postsynaptic mechanisms by which these molecules exert their action. These studies will provide new insight relevant to synaptic transmission and memory processes in the mammalian brain.

描述（由申请人提供）：兴奋性突触的活动驱动修饰是细化突触连接的极其强大的过程。海马突触传递的长时程增强（LTP）被广泛认为是记忆形成和巩固不可或缺的一部分。由于 LTP 分子的复杂性和异质性，许多细胞机制尚未完全建立。对这些基本过程的完整描述将使我们能够理解导致记忆存储和检索中断的神经系统疾病的病理学。苔藓纤维突触为海马 CA3 区域提供主要兴奋性输入之一。 CA3 的循环网络在联想记忆的存储和检索中特别重要。苔藓纤维突触对于该网络的调节至关重要，因此是海马功能的核心。苔藓纤维的可塑性表现出一些非常有趣的特性。 LTP在突触的突触前末端表达，但其诱导部位仍存在争议。最近的研究结果表明，突触后机制在诱导苔藓纤维 LTP 以及随后由 Eph 受体 - 肝配蛋白相互作用介导的跨突触信号传导至突触前方面发挥着重要作用。为了进一步探索参与这一独特途径的分子，这项研究将利用突变小鼠，其中相关蛋白质已被基因消除或突变，以破坏其信号功能。此外，我们将探索这些分子发挥作用的确切突触前和突触后机制。这些研究将为哺乳动物大脑中的突触传递和记忆过程提供新的见解。