Interaction of Opposing Forms of Synaptic Plasticity in Hippocampal Circuits

描述(申请人提供)：哺乳动物的海马体被认为是形成长期记忆的关键，然而这个大脑区域非常容易患癫痫。长时程增强和长时程增强和长时程增强抑制(LTP和LTD)--两种形式的Hebbian突触可塑性--被广泛认为是可能的信息存储的细胞机制。海马区突触的一种不同形式的突触可塑性--稳态突触可塑性--当整体电路活动改变时，驱动突触的代偿性变化以稳定网络功能。由于Hebbian形式的突触可塑性是长期存在的，这些突触效率的变化如何在面临预计会逆转它们的稳态机制的情况下如何持续尚不清楚。关于这些表面上相互冲突的可塑性过程如何相互作用的理论已经提出，但这些理论的实验支持很少，这主要是因为通常研究稳态可塑性的常规准备和时间过程不同于最广泛使用的研究Hebbian可塑性的方法(急性海马片)。为了经验性地解决这个问题，我们的实验室在急性海马片中表征了CA3-CA1突触的一种快速形式的稳态可塑性，我的初步数据显示，一种形式的Hebbian可塑性(LTD)以一种特定于输入的方式限制了这种稳态补偿。鉴于最近的工作已经将稳态过度补偿与海马区癫痫样活动的发展联系起来，这种稳态可塑性抑制调节的改变可能在颞叶癫痫的发病机制中发挥重要作用。这项提议现在将检验这样一个假设，即树突中的局部蛋白质合成，除了允许长期的信息存储外，还在允许Hebbian的可塑性限制海马突触的局部内稳态补偿方面发挥了新的作用。这一假设将在两个具体目标上得到检验。目标#1的目的是研究在相同的突触输入下，Hebbian可塑性如何与稳态可塑性相互作用。我将研究这种相互作用是否反映了检测活性变化的自稳活性传感器的抑制，或者直接反映了补偿过程的调节。目标#2的目标是确定局部树突状蛋白合成是否介导了Hebbian可塑性在相同突触输入下限制内稳态可塑性的能力。这项拟议的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定义在一个已定义的易于癫痫发生的神经回路中，内稳态和赫布过程是如何相互影响的。

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.