Interaction of Opposing Forms of Synaptic Plasticity in Hippocampal Circuits

描述（由申请人提供）：已知哺乳动物海马体对长期记忆的形成至关重要，但该脑区极易发生癫痫。长时程增强（LTP）和抑制（LTD）--两种形式的"赫布"突触可塑性--被广泛认为是海马神经回路中信息储存的可能细胞机制。海马突触的一种不同形式的突触可塑性-稳态突触可塑性-在整个回路活动发生变化时，会驱动突触的补偿性变化以稳定网络功能。由于赫布形式的突触可塑性是持久的，突触功效的这些变化如何在面对被预测会逆转它们的稳态机制时持续存在是未知的。关于这些表面上相互冲突的可塑性过程如何相互作用，已经提出了一些理论，但这些理论的实验支持是稀缺的，主要是因为常规的准备和时间过程，其中稳态可塑性经常被研究不同于那些最广泛使用的（急性海马切片）来研究赫布可塑性。为了解决这个问题的经验，我们的实验室已经表征了一种快速形式的稳态可塑性在CA3-CA1突触在急性海马切片，我的初步数据显示，一种形式的赫布可塑性（LTD）约束这种稳态补偿在输入特定的方式。鉴于最近的研究已经将稳态过度补偿与海马回路中癫痫样活动的发展联系起来，这种稳态可塑性抑制性调节的改变可能在颞叶癫痫的发病机制中起重要作用。这个建议现在将测试的假设，局部的蛋白质合成树突，除了允许持久的信息存储，发挥了新的作用，使赫布可塑性约束局部稳态补偿海马突触。这一假设将在两个具体目标中得到检验。目的#1的目的是研究如何赫布可塑性与稳态可塑性在相同的突触输入相互作用。我将检查这种相互作用是否反映了对检测活动变化的稳态活动传感器的抑制，或直接反映了对补偿过程的调节。目标#2的目标是确定局部树突蛋白合成是否介导赫布可塑性在相同突触输入下约束稳态可塑性的能力。这项研究具有重要意义和创新性，因为它提供了第一个实验方法来确定稳态和赫布过程如何在一个易于癫痫发生的神经回路中相互影响。

DESCRIPTION (provided by applicant): The mammalian hippocampus is known to be critical for the formation of long-term memories, yet this brain region is highly vulnerable to epilepsy. Long-term potentiation and depression (LTP and LTD) - two forms of "Hebbian" synaptic plasticity- are widely regarded as likely cellular mechanisms of information storage in hip- pocampal circuits. A different form of synaptic plasticity at hippocampal synapses - homeostatic synaptic plasticity -drives compensatory changes at synapses to stabilize network function when overall circuit activity changes. Since Hebbian forms of synaptic plasticity are long-lasting, how these changes in synaptic efficacy endure in the face of homeostatic mechanisms that would be predicted to reverse them is unknown. Theories have been proposed regarding how these ostensibly conflicting plasticity processes could be interacting but experimental support for these theories is scarce, largely because the conventional preparations and time- course over which homeostatic plasticity is often studied differ from those most widely used (acute hippocampal slices) to study Hebbian plasticity. To address this issue empirically, our laboratory has characterized a rapid form of homeostatic plasticity at CA3-CA1 synapses in acute hippocampal slices, and my preliminary data reveals that one form of Hebbian plasticity (LTD) constrains such homeostatic compensation in an input- specific fashion. Given that recent work has linked homeostatic overcompensation with the development of epileptoform activity in hippocampal circuits, alterations in this inhibitory regulation of homeostatic plasticity may play an important role in the pathogenesis of temporal lobe epilepsy. This proposal will now test the hypothesis that local protein synthesis in dendrites, in addition to allowing for long-lasting information storage, plays a novel role in allowing Hebbian plasticity to constrain local homeostatic compensation at hippocampal synapses. This hypothesis will be tested in two specific aims. The objective of aim #1 is to examine how Hebbian plasticity interacts with homeostatic plasticity at the same synaptic inputs. I will ex- amine whether this interaction reflects an inhibition of the homeostatic activity sensor that detects changes in activity or reflects modulation of the compensation process directly. The goal of aim #2 is to determine whether local dendritic protein synthesis mediates the ability of Hebbian plasticity to constrain homeostatic plasticity at the same synaptic inputs. This proposed research is significant and innovative because it provides the first experimental approach to define how homeostatic and Hebbian processes influence one another in a defined neural circuit prone to epileptogenesis.