Intrinsic currents modulate synaptic integration in dopamine neurons

摘要 总体目标是表征多巴胺神经元的内在特性对突触的贡献， 适应性整合具体来说，我们将确定是否以太-一个-去-去相关基因（ERG）的调制， 和/或小电导钙激活（SK）钾通道改变它们对兴奋性钾通道的响应。 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。抗精神病药可以减轻- 抑制多巴胺能信号，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爆发放电，我们提出ERG K+电流作为额外的， 新型的内在成分的突发发射。在本申请中待测试的具体假设是：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 爆发活动和2）DA神经元中ERG K+电流提供了对去极化阻滞的保护， 通过扩展确保突触驱动的DA细胞兴奋性的增加被编码和传播， DA目标“去极化阻滞”，一种持续性去极化，其中动作电位不再持续， 由于持续的钠通道失活，假设发生在内向电流， 促进爆发活动主导了减弱它的外向电流。 指示促进自发和传入驱动的爆发，并在降低ERG K+电流的存在下， 租金，以诱导去极化阻滞。具体的目的是验证预测：1）功能性ERG K+ 通道在多巴胺神经元中表达，2）SK电流的减少促进模拟自发性 和体外突触驱动的爆发活动，这种爆发活动导致去极化阻滞 除非被ERG K+电流缓解，3）DA神经元中SK和/或ERG电流的调制改变 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， vivo.复杂多室和简单多室相结合的大鼠脑电生理记录 神经模型将与用选择性药理学试剂进行的实验一起使用， 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- 理解这两种类型的突发产生的机制，因为复杂的 振荡机制和多巴胺能神经元不同区域之间的相互作用， 用作耦合振荡器。系统的集体活动可能具有根本不同的dy- 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相比。更好的 了解DA神经元的放电模式是如何调节的，可能会导致新的开发。 用于治疗多种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。

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.