An Integrated Approach to Synaptic Plasticity in the Hippocampus

海马突触可塑性的综合方法

• 批准号: 6995174
• 负责人: HAREL Zeev SHOUVAL
• 金额: $ 4.35万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6995174
• 关键词: NMDA receptors; action potentials; calcineurin; calcium flux; calmodulin dependent protein kinase; computational neuroscience; hippocampus; laboratory rat; model design /development; molecular dynamics; neural plasticity

Synaptic plasticity is believed to be an important mechanism contributing to of learning, memory, and many aspects of development. There is significant evidence that in cortex synaptic plasticity contributes significantly to receptive field development. For example, in the hippocampus there is abundant cellular and molecular information about long term potentiation (LTP) and long term depression (LTD), the cellular manifestation of long lasting synaptic plasticity. LTP and LTD can be induced by different induction paradigms that depend on presynaptic rate, on pairing presynaptic spikes with postsynaptic depolarization, and on the precise time difference between pre and postsynaptic spikes. We have recently hypothesized that a single model, which depends on calcium influx through NMDA receptors can account for these different induction paradigms. Here we propose a more detailed study of the molecular dynamics, including improved but simple models of CaMKII and Calcinurin that underlie synaptic plasticity. Based on this detailed study as well as new experimental results and measured parameters, we will develop an updated version of the unified plasticity model (UPM) that can be quantitatively tested. We hypothesize that fluctuations in molecular dynamics can play a significant role in the resulting synaptic plasticity. We propose to analyze these fluctuations and calculate their effect on the different induction paradigms of synaptic plasticity. We also propose to test experimentally the validity of a key assumption of the UPM, that the back propagating action potential has a long tail, and to measure key physiological parameters in hippocampal cells. We will use measured physiological parameters in hippocampal cells in simulating the UPM in order to create a quantitative theory appropriate for the hippocampus. The UPM will be further developed to account for the maintenance phase of synaptic plasticity. We will also test the hypothesis that homeostatic metaplasticity is crucial in attaining stable, selective and robust fixed points.

突触可塑性被认为是有助于学习、记忆和发育许多方面的重要机制。有重要的证据表明，在皮层突触可塑性显着有助于感受野的发展。例如，在海马中存在关于长时程增强（LTP）和长时程抑制（LTD）的丰富的细胞和分子信息，长时程增强和长时程抑制是持久突触可塑性的细胞表现。LTP和LTD可以通过不同的诱导范式诱导，这些诱导范式依赖于突触前速率、突触前尖峰与突触后去极化的配对以及突触前和突触后尖峰之间的精确时间差。我们最近假设，一个单一的模型，这取决于通过NMDA受体的钙内流可以解释这些不同的诱导范式。在这里，我们提出了一个更详细的研究分子动力学，包括改进，但简单的模型，CaMKII和Calcinurin的基础突触可塑性。基于这项详细的研究以及新的实验结果和测量参数，我们将开发一个更新版本的统一塑性模型（UPM），可以定量测试。我们假设，分子动力学的波动可以发挥重要作用，在突触可塑性。我们建议分析这些波动，并计算它们对突触可塑性的不同诱导范式的影响。我们还建议通过实验测试UPM的一个关键假设的有效性，即反向传播动作电位具有长尾，并测量海马细胞中的关键生理参数。我们将使用测量的生理参数在海马细胞在模拟UPM，以创建一个定量的理论适合海马。UPM将进一步发展，以解释突触可塑性的维持阶段。我们还将测试的假设，稳态亚可塑性是至关重要的，在实现稳定，选择性和强大的固定点。