Intrinsic currents modulate synaptic integration in dopamine neurons

内在电流调节多巴胺神经元的突触整合

• 批准号: 7996573
• 负责人: Carmen Castro Canavier
• 金额: $ 34.25万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7996573
• 关键词: Action Potentials; Acute; Alcohol abuse; Antipsychotic Agents; Attenuated; Brain; Calcium; Cell Nucleus; Cells; Complement; Complex; Computer Simulation; Coupled; Dependence; Development; Disease; Dopamine; Drug abuse; ERG gene; Electric Stimulation; Ensure; Ethers; Exhibits; Frequencies; Generations; Hodgkin Disease; In Vitro; Kinetics; Lead; Masks; Mediating; Midbrain structure; Modeling; Morphologic artifacts; Neurons; Parkinson Disease; Pattern; Potassium Channel; Procedures; Process; Property; Protocols documentation; Psychotic Disorders; Publishing; Rattus; Regulation; Rewards; Role; SK potassium channel; Scheme; Schizophrenia; Signal Transduction; Simulate; Slice; Sodium Channel; Stimulus; Synapses; System; Testing; Therapeutic; Time; channel blockers; design; dopaminergic neuron; improved; in vitro activity; in vivo; neural model; new therapeutic target; novel; research study; response; voltage; voltage clamp

DESCRIPTION (provided by applicant): The overall objective is to characterize the contribution of the intrinsic properties of dopamine neurons to synaptic integration. Specifically, we will determine whether modulation of the ether-a-go-go-related gene (ERG) and/or the small conductance calcium-activated (SK) potassium channels alters their response to excitatory synaptic input. Bursts in dopamine neurons are thought to convey the reward prediction and salience signals. Schizophrenia is thought to result from disordered dopaminergic signaling. Antipsychotics attenuate the disordered dopaminergic signal, relieving psychosis, and usually partially block the K+ ERG current. The SK current masks background burst firing in dopamine neurons, and we propose the ERG K+ current as an additional, novel intrinsic component of burst firing. The specific hypotheses to be tested in this application are that: 1) the level of spontaneous bursting activity determines the ability of excitatory afferent inputs to trigger time-locked bursting activity and 2) that ERG K+ current in DA neurons provides a safeguard from depolarization block, and by extension ensures that synaptically driven increases in DA cell excitability are encoded and propagated to DA targets. "Depolarization block", a persistent depolarization in which action potentials are no longer sustained due to persistent sodium channel inactivation, is hypothesized to occur when the inward currents that promote bursting activity dominate the outward currents that attenuate it. A decrease in SK current is predicted to facilitate both spontaneous and afferent-driven bursting, and in the presence of reduced ERG K+ cur- rent, to induce depolarization block. The specific aims are to test the predictions that 1) functional ERG K+ channels are expressed in dopamine neurons, 2) a reduction in SK current facilitates simulated spontaneous and synaptically-driven bursting activity in vitro, and that this bursting activity results to depolarization block unless relieved by the ERG K+ current, and 3) modulation of SK and/or ERG currents in DA neurons alters their ability to produce both spontaneous bursts as well as bursts in response to excitatory synaptic input in vivo. Electrophysiological recordings in rat brain combined with both complex multi-compartmental and simple neural models will be utilized in concert with experiments conducted with selective pharmacological agents to titrate the contribution of these currents to dopaminergic signaling. The modeling component is required to understand the mechanisms underlying the generation of both types of bursting because of the complexity of the oscillatory mechanisms and the interactions between different regions of the dopaminergic neuron that likely function as coupled oscillators. The collective activity of the system is likely to have fundamentally different dynamics in vivo compared to in vitro because of the interaction of intrinsic and synaptic mechanisms. A better understanding of how the firing pattern of DA neurons is regulated could result in the development of novel therapeutic targets for treating a variety of DA related disorders including Parkinson's disease, schizophrenia, drug and alcohol abuse. Both experiments and computer modeling will be used to characterize the contributions of the ether-a-go-go-related gene (ERG) and small conductance (SK) potassium channels to the electrical activity of midbrain dopamine neurons. A better understanding of this activity, and specifically of the role of these currents in regulating the firing pattern in these neurons, may lead to improved therapeutics for both Parkinson's and schizophrenia, as well as other disorders involving dopaminergic signaling such as drug abuse.

描述（由申请人提供）：总体目标是表征多巴胺神经元对突触整合的内在特性的贡献。具体而言，我们将确定对Ether-A-Go相关基因（ERG）和/或小电导钙激活（SK）钾通道的调节是否改变了其对兴奋性突触输入的反应。人们认为多巴胺神经元中的爆发传达了奖励预测和显着信号。精神分裂症被认为是由于多巴胺能信号传导而引起的。抗精神病药可减轻无序的多巴胺能信号，缓解精神病，通常会部分阻断K+ ERG电流。 SK电流掩盖了多巴胺神经元中的爆发爆发，我们提出ERG K+电流是爆发的附加新型内在组成部分。 The specific hypotheses to be tested in this application are that: 1) the level of spontaneous bursting activity determines the ability of excitatory afferent inputs to trigger time-locked bursting activity and 2) that ERG K+ current in DA neurons provides a safeguard from depolarization block, and by extension ensures that synaptically driven increases in DA cell excitability are encoded and propagated to DA targets. “去极化阻滞”是一种持续的去极化，在该持续的去极化中，由于持续的钠通道失活而不再持续的动作电位，因此当促进破裂活性的内向电流占据了衰减的外向电流时，就会发生。预计SK电流的降低将促进自发和传入驱动的爆发，并且在降低的ERG K+ Cur-Curland存在下，以诱导去极化块。 The specific aims are to test the predictions that 1) functional ERG K+ channels are expressed in dopamine neurons, 2) a reduction in SK current facilitates simulated spontaneous and synaptically-driven bursting activity in vitro, and that this bursting activity results to depolarization block unless relieved by the ERG K+ current, and 3) modulation of SK and/or ERG currents in DA neurons alters their ability to produce both spontaneous响应体内兴奋性突触输入，爆发和爆发。大鼠脑中的电生理记录以及复杂的多室和简单神经模型的结合，将与选择性药理学剂进行的实验一起使用，以滴定这些电流对多巴胺能信号的贡献。由于振荡机制的复杂性以及多巴胺能神经元的不同区域之间的相互作用可能起作用，因此需要建模成分才能理解两种类型爆发的机制。与体外相比，由于固有和突触机制的相互作用，该系统的集体活性在体内可能具有根本不同的动力学。更好地理解DA神经元的射击模式如何受到调节可能导致新的治疗靶标，以治疗各种DA相关疾病，包括帕金森氏病，精神分裂症，药物和酒精滥用。实验和计算机建模都将用于表征与中脑多巴胺神经元的电活动的乙醚-A-GO相关基因（ERG）（ERG）和小电导（SK）钾通道的贡献。更好地了解这项活动，特别是这些电流在调节这些神经元中的发射模式中的作用，可能会改善帕金森氏症和精神分裂症的治疗方法，以及其他涉及多巴胺能信号（如药物滥用）的疾病。