Intrinsic currents modulate synaptic integration in dopamine neurons

摘要 总的目标是表征多巴胺神经元的内在特性对突触的贡献。 APTIC整合。具体地说，我们将确定乙醚-a-go-go相关基因(ERG)的调制 和/或小电导钙激活(SK)钾通道改变其对兴奋的反应 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著信号。 精神分裂症被认为是多巴胺能信号紊乱的结果。抗精神病药物可以减轻疾病- 抑制多巴胺能信号，缓解精神病，通常部分阻断K ERG电流。SK海流 掩蔽多巴胺神经元的背景爆发式放电，我们提出ERG K电流作为额外的， 爆炸发射的新型本征部件。在本申请中要检验的具体假设是：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 2)DA神经元的ERG K电流对去极化阻断有保护作用； 通过扩展，确保DA细胞兴奋性的突触驱动增加被编码并传播到 地区检察官的目标。“去极化阻断”，一种持续的去极化，在这种情况下动作电位不再- 被认为是由于持续的钠通道失活，假设发生在内向电流 促进爆发性活动控制减弱它的外向电流。SK电流的下降是预估的 以促进自发和传入驱动的爆发，并在ERG K-Cur降低的情况下- 房租，诱导去极化阻断。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电流的减少促进了模拟的自发 和突触驱动的体外爆发活动，这种爆发活动导致去极化阻断 除非被ERG K电流缓解，否则3)DA神经元中SK和/或ERG电流的调制会改变 它们对兴奋性突触输入既产生自发爆发又产生爆发的能力 活着。复合多隔室与单纯电生理记录相结合的大鼠脑电生理记录 神经模型将与使用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的贡献。建模组件需要取消- 理解这两种猝发产生的潜在机制，因为 振荡机制和多巴胺能神经元不同区域之间的相互作用 起耦合振荡器的作用。该系统的集体活动很可能具有根本不同的性质。 体内动力学与体外动力学相比，是因为内在机制和突触机制的相互作用。更好的 了解DA神经元的放电模式是如何调节的，可能会导致新的 治疗多种多巴胺相关疾病的治疗目标，包括帕金森氏病，精神分裂症， 吸毒和酗酒。

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.