Consequences of HCN/h pacemarker channel deficency for cortico-basal ganglia circuit function

HCN/h 起搏器通道缺陷对皮质基底节回路功能的影响

• 批准号: 257996791
• 负责人: Professor Dr. Dirk Isbrandt
• 金额: --
• 依托单位: Institut für Molekulare und Verhaltensneurowissenschaften
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/257996791?language=en
• 关键词: Consequences; HCN; pacemarker; channel; deficency

Parkinson¿s disease (PD) is a common, debilitating neurodegenerative disorder characterized by profound circuit dysfunction in basal ganglia nuclei. The motor disability is specifically associated with the emergence of exaggerated beta (11-30 Hz) oscillations and synchronous, rhythmic spiking of neurons in basal ganglia. Abnormal beta oscillations develop after chronic dopamine depletion, are largely coherent in cortex and basal ganglia nuclei, and may be normalized by dopamine replacement therapies. Aberrant basal ganglia beta oscillations likely reflect synchronized rhythmic neuronal activities generated by local microcircuits, which become pathologically amplified within basal ganglia-cortical loops. However, the specific molecular and circuit mechanisms of this synchronization are not well understood. A crucial element of all basal ganglia microcircuits are pacemaker neurons, which are thought to be necessary for the generation of the normal rhythmic local and network activity sustaining motor function. These neurons can generate intrinsic membrane potential oscillations that strongly bias the timing of their action potential output. Pacemakers in the basal ganglia are very diverse. They range from the slow-spiking dopamine neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) to the fast-spiking (over 20 Hz) GABAergic substantia nigra pars reticulata (SNr) neurons and the cholinergic striatal interneurons (tonically active neurons or TANs.) Each of these cells expresses HCN channels, which produce the hyperpolarization-activated Ih-current. Ih can cause membrane resonance, an intrinsic biophysical property supporting pacemaker spiking. Altered Ih amplitude or HCN subunit expression is seen in many neurological disease states and disease models. To better understand basal ganglia pacemaker neurons at the cellular level, and their integration at the network and behavioral levels, we will alter their intrinsic membrane properties by genetic suppression of HCN/h channel activity. We hypothesize that a loss of function of HCN/h channels will specifically alter the pacemaker properties of these neurons and, in changing their firing patterns, alter synaptic and network activities, thus affecting both cognitive and motor function. We will use a combination of conditional expression of a dominant-negative HCN subunit, in vitro and in vivo electrophysiology, and behavioral analyses to characterize the consequences of attenuated HCN/h currents. We will record unit and network activity in key basal ganglia nuclei such as the dorsal striatum, the external segment of the globus pallidus (GPe), the subthalamic nucleus (STN), and the VTA/SN in both acute and awake-behaving preparations. In addition, we will investigate whether and how altered firing patterns and consequently the metabolic load of SNc neurons influence the vulnerability of these neurons in chronic PD models.

帕金森S病(PD)是一种常见的、衰弱的神经退行性疾病，其特征是基底节核团严重的回路功能障碍。运动障碍与基底节神经元出现夸大的β(11-30赫兹)振荡和同步、有节奏的尖峰有关。异常的β振荡在慢性多巴胺耗竭后发生，在皮质和基底节核团中基本一致，并可通过多巴胺替代疗法恢复正常。异常的基底节β振荡可能反映了由局部微电路产生的同步节律性神经元活动，在基底节-皮质环内被病理放大。然而，这种同步的具体分子和电路机制还不是很清楚。起搏神经元是所有基底节微电路的关键元件，它们被认为是维持运动功能的正常、有节奏的局部和网络活动所必需的。这些神经元可以产生固有的膜电位振荡，强烈地偏离其动作电位输出的时间。基底节的起搏器种类繁多。它们的范围从黑质致密部(SNC)和腹侧被盖区(VTA)的慢峰神经元到快峰(20赫兹以上)GABA能黑质网状部(SNR)神经元和纹状体间胆碱能神经元(紧张性神经元或TAN)。这些细胞中的每一个都表达HCN通道，从而产生超极化激活的氢电流。IH可引起膜共振，这是一种支持起搏器尖峰的内在生物物理特性。在许多神经系统疾病状态和疾病模型中都可以看到iH幅度或hcn亚单位表达的改变。为了在细胞水平上更好地了解基底节起搏神经元，以及它们在网络和行为水平上的整合，我们将通过基因抑制HCN/h通道活动来改变它们的固有膜特性。我们假设，HCN/h通道功能的丧失将特异性地改变这些神经元的起搏特性，并在改变其放电模式时改变突触和网络活动，从而影响认知和运动功能。我们将结合显性负性HCN亚基的条件表达，体外和体内电生理学，以及行为分析来表征减弱的HCN/h电流的后果。我们将记录急性和清醒状态准备中的关键基底节核团，如背侧纹状体、苍白球外段(GPE)、丘脑底核(STN)和VTA/SN的单位和网络活动。此外，我们将研究在慢性帕金森病模型中，放电模式的改变以及由此导致的黑质神经元的代谢负荷是否以及如何影响这些神经元的脆弱性。