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，对它的研究一直很少。我们的实验室最近描述了一种新的形式的内质可塑性，在下丘脑锥体神经元的兴奋性，海马体的主要输出途径。突触刺激后爆发式放电的可塑性不依赖于AMPA或NMDA受体，而是依赖于代谢性M受体和谷氨酸受体(mAChRs和mGluRs)的协同激活。通过在树突状细胞刺激过程中激活不同亚型的代谢性受体，诱导了对爆发式放电的持久增强或抑制(Moore等人，Neuron 2009)。虽然这一机制可能对来自海马体的信息传输的保真度产生深远的影响，但突发性可塑性表达的机制仍不清楚。我们现在正在研究CA1神经元是否发生爆发性可塑性。使用全细胞电流钳和细胞附着式电压钳记录，我们发现，虽然这些神经元可以诱导爆发性可塑性，但CA1和下丘脑对爆发性可塑性的药理作用不同。在爆发式放电的下丘脑神经元中，mGluR1和mAChRs的协同激活才能引起爆发式放电的持续增加，而mGluR5则介导了对爆发式放电的抑制。然而，初步数据表明，在规则放电的CA1神经元中，mGluR5介导的爆发式放电增强，mGluR1和mAChRs的拮抗并不阻止爆发式放电的诱导。除了阐明促进爆裂可塑性诱导的药理学过程外，我还将探讨可塑性如何在CA1中表达。是通过上调去极化电导，如电压门控钠通道或钙通道，通过下调钾通道，还是两者的组合，来实现更强的爆发式放电？使用许多电压门控和钙激活通道的选择性阻滞剂，我将记录爆发性可塑性诱导后的特定离子电流，以确定可塑性表达的分子一致性。进一步研究爆发性可塑性的机制将对内在可塑性在调节海马区整合和输出中的作用产生有价值的见解，并可能进一步提出新的信息存储机制。 公共卫生相关性： 这个项目研究了海马体中一种新的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，关于神经元信号变化与记忆联系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疾病(如阿尔茨海默氏症和痴呆症)提供有价值的见解。

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.