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: 8197705
• 负责人: Carmen Castro Canavier
• 金额: $ 34.07万
• 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/8197705
• 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; abstracting; channel blockers; design; dopaminergic neuron; improved; in vitro activity; in vivo; neural model; new therapeutic target; novel; research study; response; voltage; voltage clamp

Abstract The overall objective is to characterize the contribution of the intrinsic properties of dopamine neurons to syn- aptic 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 disor- dered 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 sus- tained 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 pre- dicted 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 un- derstand 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 dy- namics 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.

抽象的 总体目的是表征多巴胺神经元对合成的内在特性的贡献 智力整合。具体而言，我们将确定是否调制Ether-A-Go-Go相关基因（ERG） 和/或小电导钙激活（SK）钾通道改变了它们对兴奋的反应 突触输入。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。抗精神病患者减轻了这些迷恋 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 掩盖背景在多巴胺神经元中爆发，我们提出ERG K+电流作为附加的， 爆发的新型内在组成部分。在本应用程序中要测试的特定假设是：1） 自发爆发活动的水平决定了兴奋性传入输入触发时间锁定的能力 爆发活动和2）DA神经元中的ERG K+电流提供了防止去极化块的保障，并且 扩展可确保对DA细胞兴奋性的突触驱动的增加进行编码并传播到 DA目标。 “去极化阻滞”，这是一种持续的去极化，其中动作电位不再是 由于持续的钠通道失活而导致的，当向内电流的向内电流中发生 促进爆发活动主导着衰减它的外流。 SK电流的降低是前 被征用是为了促进自发和传入驱动的爆发，并且在降低的ERG K+ Cur-存在下 租金，诱导去极化块。具体目的是测试预测1）功能性ERG K+ 通道在多巴胺神经元中表达，2）SK电流的降低促进了模拟的自发性 并在体外突触驱动的爆发活性，并且这种爆发活性导致去极化阻滞 除非由ERG K+电流缓解，而3）DA神经元中的SK和/或ERG电流的调节变化 它们产生自发爆发的能力以及响应于兴奋性突触输入的能力 体内。大鼠大脑中的电生理记录以及复杂的多室和简单 神经模型将与选择性药理学剂进行的实验一起使用 滴定这些电流对多巴胺能信号的贡献。需要建模组件才能取消 阐明了两种类型爆发的产生的机制，因为 振荡机制以及多巴胺能神经元不同区域之间的相互作用可能 功能充当耦合振荡器。该系统的集体活动可能具有根本不同的dy- 由于内在和突触机制的相互作用，体内的名称与体外相比。更好 了解如何调节DA神经元的射击模式可能导致新颖的发展 治疗各种DA相关疾病在内的治疗靶点，包括帕金森氏病，精神分裂症， 毒品和酒精滥用。