Role of metabotropic receptors in regulating intrinsic plasticity in hippocampus

代谢型受体在调节海马内在可塑性中的作用

• 批准号: 8047991
• 负责人: Austin Robert Graves
• 金额: $ 3.08万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8047991
• 关键词: AMPA Receptors; Address; Affect; Alzheimer' s Disease; Area; Brain; Calcium; Calcium Channel; Cells; Cholinergic Receptors; Complex; Data; Dementia; Dialysis procedure; Global Change; Glutamate Receptor; Hippocampus (Brain); Individual; Information Storage; Ion Channel; Laboratories; Learning; Link; Measures; Mediating; Memory; Memory impairment; Molecular; Molecular Target; Muscarinic Acetylcholine Receptor; N-Methyl-D-Aspartate Receptors; Neurons; Output; Pathway interactions; Pattern; Pharmacology; Physiological Processes; Potassium Channel; Process; Regulation; Role; Signal Transduction; Slice; Sodium Channel; Synapses; Synaptic plasticity; experience; hippocampal pyramidal neuron; inhibitor/antagonist; insight; novel; public health relevance; receptor; research study; response; voltage; voltage clamp

DESCRIPTION (provided by applicant): Though intrinsic plasticity is an important mechanism by which the brain may encode and store information, it has been largely understudied in the learning and memory field. Our lab recently described a novel form of intrinisic plasticity in the excitability of pyramidal neurons in subiculum, the primary output pathway of the hippocampus. Plasticity of burst firing followed theta-patterned synaptic stimulation and did not depend on AMPA or NMDA receptors, but rather on synergistic activation of metabotropic muscarinic and glutamate receptors (mAChRs and mGluRs). By activating different sub-types of metabotropic receptors during dendritic stimulation, a long lasting enhancement or suppression of burst firing was induced (Moore et al., Neuron 2009). While this mechanism may exert profound influence of the fidelity of information transfer from the hippocampus, the mechanisms underlying burst plasticity expression remain unknown. We are now studying whether burst plasticity occurs in CA1 neurons. Using whole-cell current-clamp and cell-attached voltage- clamp recordings, we found that while burst plasticity can be induced in these neurons, the pharmacology of burst plasticity differed between CA1 and subiculum. In burst-firing subicular neurons, synergistic activation of mGluR1 and mAChRs was required to induce a long lasting increase in burst firing, whereas mGluR5 mediated a suppression of burst firing. In regular-spiking CA1 neurons, however, preliminary data suggest that mGluR5 mediated enhanced burst firing and antagonism of mGluR1 and mAChRs did not block the induction of increased burst firing. In addition to elucidating the pharmacological processes contributing to burst plasticity induction, I will also explore how plasticity is expressed in CA1. Is increased burst firing achieved by upregulating a depolarizing conductance, such as a voltage-gated sodium or calcium channel, by downregulating a potassium channel, or a combination of both? Using selective blockers for numerous voltage- gated and calcium-activated channels, I will record specific ionic currents following burst plasticity induction to determine the molecular identity of plasticity expression. Further scrutiny of the mechanisms underlying burst plasticity will yield valuable insight regarding the role of intrinsic plasticity in modulating hippocampal integration and output, and may further suggest novel mechanisms for information storage. PUBLIC HEALTH RELEVANCE: This project studies the cellular underpinnings of a novel form of information storage in the hippocampus, a crucial brain area involved in memory formation. Presently, very little is known regarding the molecular mechanisms linking changes in neuronal signaling to memory. Elucidating these mechanisms will increase our understanding of the complex processes behind memory and may yield valuable insights into pathological conditions associated with memory deficits, such as Alzheimer's and dementia.

描述（由申请人提供）： 尽管固有​​的可塑性是大脑可以编码和存储信息的重要机制，但它在学习和记忆领域已大大研究。我们的实验室最近描述了一种新型的固有可塑性形式，它在海马的主要输出途径下锥体神经元的兴奋性中。爆发的可塑性遵循theta形式的突触刺激，不依赖AMPA或NMDA受体，而是取决于代谢性毒蕈碱和谷氨酸受体（MACHRS和MGLURS）的协同激活。通过在树突刺激过程中激活不同的代谢受体的亚型亚型，诱发了持久的增强或抑制爆发放电（Moore等，Neuron，2009）。虽然这种机制可能会产生信息传递从海马的忠诚度的深远影响，但爆发塑性表达的机制仍然未知。我们现在正在研究CA1神经元中是否发生爆发可塑性。使用全细胞电流钳和细胞连接的电压夹记录，我们发现虽然可以在这些神经元中诱导爆发塑性，但CA1和亚图中的爆发可塑性的药理学却有所不同。在发射爆发的亚地区神经元中，需要MGLUR1和MACHRS的协同激活来诱导持久爆发的持久增加，而MGLUR5则介导了对爆发的抑制。然而，在常规尖刺的CA1神经元中，初步数据表明MGLUR5介导的增强的MGLUR1和MACHR的爆发爆发和拮抗作用并没有阻止爆发增加的诱导。除了阐明导致爆发可塑性诱导的药理学过程外，我还将探讨在CA1中如何表达可塑性。通过下调钾通道或两者的组合，是否会通过上调去极化电导来增加爆发的发射，例如电源门控钠或钙通道。使用选择性阻滞剂进行大量电压和钙激活的通道，我将记录爆发塑性诱导后的特定离子电流，以确定可塑性表达的分子身份。对爆发可塑性的基础机制的进一步审查将对内在可塑性在调节海马整合和输出中的作用产生有价值的见解，并可能进一步提出用于信息存储的新型机制。 公共卫生相关性： 该项目研究海马中新型信息存储形式的细胞基础，海马是与记忆形成有关的关键大脑区域。目前，关于将神经元信号变化与记忆联系起来的分子机制知之甚少。阐明这些机制将增加我们对记忆背后复杂过程的理解，并可能对与记忆缺陷相关的病理状况（例如阿尔茨海默氏症和痴呆症）产生有价值的见解。