Intrinsic currents modulate synaptic integration in dopamine neurons

描述（由申请人提供）：总体目标是表征多巴胺神经元的内在特性对突触整合的贡献。具体来说，我们将确定是否以太-一个-去-去相关基因（ERG）和/或小电导钙激活（SK）钾通道的调制改变他们的兴奋性突触输入的反应。多巴胺神经元的爆发被认为传达了奖励预测和显着性信号。精神分裂症被认为是由多巴胺能信号紊乱引起的。抗精神病药物减弱了紊乱的多巴胺能信号，缓解精神病，通常部分阻断K+ ERG电流。SK电流掩盖了多巴胺神经元的背景突发放电，我们提出ERG K+电流作为突发放电的一个额外的，新颖的内在组成部分。在本申请中待检验的具体假设为：1）自发爆发活动的水平决定兴奋性传入输入触发时间锁定爆发活动的能力，2）DA神经元中的ERG K+电流提供了一种保护措施，避免去极化阻滞，并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至DA靶点。“去极化阻滞”是一种持续的去极化，其中由于持续的钠通道失活而导致动作电位不再持续，假设当促进爆发活动的内向电流占主导地位时发生，外向电流减弱爆发活动。预计SK电流的减少有助于自发和传入驱动的爆发，并且在存在降低的ERG K+电流的情况下，诱发去极化阻滞。具体目的是测试以下预测：1）功能性ERG K+通道在多巴胺神经元中表达，2）SK电流的减少促进体外模拟的自发和突触驱动的爆发活动，并且除非ERG K+电流缓解，否则这种爆发活动导致去极化阻滞，和3）DA神经元中SK和/或ERG电流的调节改变了它们在体内产生自发爆发以及响应兴奋性突触输入的爆发的能力。将利用大鼠脑中的电生理记录结合复杂的多室和简单的神经模型，与选择性药理学试剂进行的实验相结合，以滴定这些电流对多巴胺能信号传导的贡献。由于振荡机制的复杂性和多巴胺能神经元不同区域之间的相互作用（可能作为耦合振荡器），需要建模组件来理解这两种类型爆发产生的机制。由于内在机制和突触机制的相互作用，系统的集体活动在体内与体外相比可能具有根本不同的动力学。更好地了解DA神经元的放电模式是如何调节的，可能会导致开发新的治疗靶点，用于治疗各种DA相关疾病，包括帕金森病，精神分裂症，药物和酒精滥用。实验和计算机建模将被用来表征醚-一个-去-去相关基因（ERG）和小电导（SK）钾通道的中脑多巴胺神经元的电活动的贡献。更好地理解这种活动，特别是这些电流在调节这些神经元中的放电模式中的作用，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传导的疾病，如药物滥用。

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.