Role of metabotropic receptors in regulating intrinsic plasticity in hippocampus

描述（由申请人提供）： 虽然内在可塑性是大脑编码和存储信息的重要机制，但在学习和记忆领域，它的研究还很不够。我们的实验室最近描述了一种新形式的内在可塑性的兴奋性下托锥体神经元，海马的主要输出通路。突发放电的可塑性θ模式的突触刺激，并不依赖于AMPA或NMDA受体，而是代谢型毒蕈碱和谷氨酸受体（mAChRs和mGluRs）的协同激活。通过在树突刺激期间激活不同亚型的代谢型受体，诱导了爆发放电的长期持续增强或抑制（摩尔等人，Neuron 2009）。虽然这一机制可能会产生深刻的影响，从海马的信息传递的保真度，突发可塑性表达的机制仍然未知。我们现在正在研究是否爆发可塑性发生在CA1神经元。使用全细胞电流钳和细胞贴附电压钳记录，我们发现，虽然可以在这些神经元中诱导爆发可塑性，但爆发可塑性的药理学在CA1和下托之间不同。在爆发式放电的下托神经元，协同激活mGluR1和mAChRs需要诱导一个持久的增加爆发式放电，而mGluR5介导的抑制爆发式放电。然而，在常规尖峰CA 1神经元中，初步数据表明，mGluR5介导增强的爆发放电，并且mGluR1和mAChRs的拮抗作用并不阻断增加的爆发放电的诱导。除了阐明有助于突发可塑性诱导的药理学过程，我还将探讨可塑性如何在CA1中表达。是否通过上调去极化电导（如电压门控钠或钙通道）、下调钾通道或两者的组合来实现猝发放电增加？使用许多电压门控和钙激活通道的选择性阻断剂，我将记录突发可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。进一步研究爆发可塑性的机制将产生有价值的见解内在可塑性在调节海马整合和输出的作用，并可能进一步提出新的信息存储机制。 公共卫生相关性： 该项目研究海马体中一种新型信息存储形式的细胞基础，海马体是参与记忆形成的关键大脑区域。目前，关于神经元信号与记忆之间的分子机制还知之甚少。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（如阿尔茨海默氏症和痴呆症）产生有价值的见解。

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.