Interaction of Opposing Forms of Synaptic Plasticity in Hippocampal Circuits

海马回路中突触可塑性的相反形式的相互作用

• 批准号: 8401549
• 负责人: Adam James Iliff
• 金额: $ 3.29万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8401549
• 关键词: Acute; Address; Amines; Animals; Area; Biological Neural Networks; Brain; Brain region; Clinical; Conflict (Psychology); Data; Dendrites; Development; Epilepsy; Epileptogenesis; Episodic memory; Etiology; Feedback; Financial compensation; Future; Goals; Hippocampus (Brain); Human; Individual; Information Storage; Laboratories; Learning; Left; Link; Literature; Long-Term Depression; Long-Term Potentiation; Mediating; Memory; Mental Depression; Metabolic; Modification; Molecular; Neurons; Pathogenesis; Pattern; Play; Population; Preparation; Process; Protein Biosynthesis; Proteins; Regulation; Relative (related person); Research; Research Personnel; Role; Seizures; Slice; Structure; Synapses; Synaptic plasticity; Temporal Lobe Epilepsy; Testing; Time; Translations; Work; cost; innovation; long term memory; man; neural circuit; neuronal cell body; novel; novel therapeutics; postsynaptic; public health relevance; relating to nervous system; response; sensor; theories

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.

描述（由申请人提供）：众所周知，哺乳动物的海马体对长期记忆的形成至关重要，但这一大脑区域极易受到癫痫的影响。长期增强和抑制（LTP和LTD）是“Hebbian”突触可塑性的两种形式，被广泛认为是髋关节-海马回路中信息储存的细胞机制。海马突触的另一种形式的突触可塑性——稳态突触可塑性——驱动突触的代偿性变化，以稳定整个回路活动变化时的网络功能。由于Hebbian形式的突触可塑性是持久的，这些突触功效的变化是如何在面对预计会逆转它们的稳态机制时持续下去的，这是未知的。关于这些表面上相互冲突的可塑性过程如何相互作用的理论已经提出，但这些理论的实验支持很少，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研究Hebbian可塑性的最广泛使用的方法（急性海马切片）。为了从经验上解决这一问题，我们的实验室已经表征了急性海马切片中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）以输入特定的方式限制了这种稳态补偿。鉴于最近的研究将稳态过度补偿与海马体回路中癫痫样活动的发展联系起来，这种对稳态可塑性的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。这一提议将验证树突中局部蛋白质合成的假设，除了允许持久的信息存储外，在允许Hebbian可塑性约束海马突触局部稳态补偿方面起着新的作用。这一假设将在两个具体目标中得到检验。目的1是研究在相同的突触输入下，Hebbian可塑性是如何与稳态可塑性相互作用的。我将研究这种相互作用是否反映了检测活动变化的稳态活动传感器的抑制或直接反映了补偿过程的调制。目的2的目标是确定局部树突蛋白合成是否介导Hebbian可塑性在相同突触输入下约束稳态可塑性的能力。这项研究具有重要的意义和创新性，因为它提供了第一个实验方法来定义稳态过程和Hebbian过程如何在一个容易发生癫痫的神经回路中相互影响。