Modulation of calcium-mediated plasticity signals in dendritic spines

突触传递受大脑中钙依赖性可塑性信号的调节。大多数钙信号 由神经活动激活的电压依赖性钙通道引起。广泛的研究表明， 确定了特定的活动模式如何驱动可塑性。例如，在尖峰定时相关的情况下， 可塑性，突触能输入和突触后AP之间的时序决定了 可塑性。虽然由活动诱发的钙信号对于可塑性的产生是必要的，但是， 钙信号和特定的可塑性反应之间的关系仍不清楚。在本提案中，我们假设， 解释了由使用荧光钙引起的钙信号测量中的失真 指示剂将阐明钙信号如何激活突触可塑性。 为了解决这一假设，我们建立了一种测量钙电流的方法， 与荧光钙指示剂所施加的失真无关。在目标1中，我们将制定一个完整的 突触钙处理的模型，使生理钙信号的测量。在目标2中，我们将 应用这些方法来了解突触能输入和突触后作用的同时激活 电位驱动钙信号，以及它是否可以解释尖峰时间依赖性可塑性的时间过程。 抑制可以在空间上限制和阻止可塑性的发生。此功能对于关联 在人类神经系统疾病中被破坏。然而，方法上的挑战阻碍了 可塑性抑制控制机制的研究。在目标3中，我们将联合收割机结合我们的方法 用两种新技术测量钙电流， 突触钙信号的抑制控制。我们将测量抑制如何调节突触钙信号 并确定这种调制对可塑性诱导的影响。 总之，这一建议提供了一个重要的方法创新，将大大推进我们的工作。 了解基本的神经功能。这些调查的结果将提供一个框架， 了解突触可塑性是如何调节的，并可能指导治疗的发展， 神经变性疾病

Synaptic transmission is regulated by calcium-dependent plasticity signals in the brain. Most calcium signals arise from voltage-dependent calcium channels which are activated by neural activity. Extensive research has identified how particular patterns of activity drive plasticity. For example, in the case of spike-timing dependent plasticity, the timing between glutamatergic input and postsynaptic APs determines the sign and magnitude of plasticity. Although calcium signals evoked by activity are necessary for the generation of plasticity, the mapping between calcium signals and specific plasticity responses is still unclear. In this proposal, we hypothesize that accounting for distortions in measurements of calcium signals imposed by the use of fluorescent calcium indicators will elucidate how calcium signals activate synaptic plasticity. To address this hypothesis, we have established a method of measuring calcium currents, which are independent of the distortion imposed by fluorescent calcium indicators. In Aim 1, we will develop a complete model of synaptic calcium handling to enable measurements of physiological calcium signals. In Aim 2, we will apply these methods to understand how coincident activation of glutamatergic input and postsynaptic action potentials drives calcium signals and whether it can explain the time course of spike-timing dependent plasticity. Inhibition can spatially restrict and prevent plasticity from occurring. This function is important for associative learning and is disrupted in human neurological diseases. However, methodological challenges have prevented investigations of the mechanisms of inhibitory control of plasticity. In Aim 3, we will combine our method of measuring calcium currents with two new technologies that enable extremely detailed investigations of inhibitory control of synaptic calcium signals. We will measure how inhibition modulates synaptic calcium signals and determine the effect of this modulation on the induction of plasticity. In summary, this proposal provides an important methodological innovation that will significantly progress our understanding of fundamental neural functions. The results of these investigations will provide a framework for understanding how synaptic plasticity is regulated and may guide the development of therapies for neurogenerative disease.