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 总体目标是表征多巴胺神经元的内在特性对同步的贡献。 aptic整合。具体来说，我们将确定是否调节了 ether-a-go-go 相关基因 (ERG) 和/或小电导钙激活 (SK) 钾通道改变其对兴奋性的反应 突触输入。多巴胺神经元的爆发被认为传达了奖励预测和显着信号。 精神分裂症被认为是由多巴胺能信号传导紊乱引起的。抗精神病药可减轻精神障碍 释放多巴胺能信号，缓解精神病，并且通常部分阻断 K+ ERG 电流。 SK电流 掩盖多巴胺神经元的背景爆发放电，我们建议 ERG K+ 电流作为附加的， 突发射击的新颖内在成分。本申请要测试的具体假设是：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，2) DA 神经元中的 ERG K+ 电流提供了免受去极化阻滞的保护，以及 通过扩展，确保突触驱动的 DA 细胞兴奋性增加被编码并传播到 发展议程目标。 “去极化阻滞”，一种持续的去极化，其中动作电位不再持续 由于持续的钠通道失活而导致的，假设当内向电流 促进爆发活动主导削弱它的外向电流。 SK电流的减少是预 旨在促进自发和传入驱动的爆发，并且在 ERG K+ 电流降低的情况下 租金，以诱发去极化阻滞。具体目标是测试以下预测：1) 功能性 ERG K+ 通道在多巴胺神经元中表达，2）SK电流的减少有利于模拟自发 和体外突触驱动的爆发活动，并且这种爆发活动导致去极化阻滞 除非通过 ERG K+ 电流缓解，并且 3) DA 神经元中 SK 和/或 ERG 电流的调节改变 它们产生自发爆发以及响应兴奋性突触输入的爆发的能力 体内。大鼠脑电生理记录结合复杂多室和简单 神经模型将与选择性药物制剂的实验相结合，以 滴定这些电流对多巴胺能信号传导的贡献。建模组件需要取消 由于突发的复杂性，了解两种类型突发的生成机制 振荡机制和多巴胺能神经元不同区域之间的相互作用可能 用作耦合振荡器。该系统的集体活动可能具有根本不同的动态 由于内在机制和突触机制的相互作用，体内的动力学与体外的动力学进行了比较。更好的 了解 DA 神经元的放电模式如何调节可能会导致新的 治疗多种 DA 相关疾病的治疗靶点，包括帕金森病、精神分裂症、 吸毒和酗酒。