HCN2 and HCN1 channels govern the regularity of autonomous pacemaking and synaptic resetting in globus pallidus neurons
HCN2 and HCN1 channels govern the regularity of autonomous pacemaking and synaptic resetting in globus pallidus neurons
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DOI：
10.1523/jneurosci.2162-04.2004
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发表时间：
2004-11-03
影响因子：
5.3
通讯作者：
Surmeier, DJ
中科院分区：
文献类型：
--
作者：
Chan, CS;Shigemoto, R;Surmeier, DJ
苍白球 (GP) 是控制运动行为的基底神经节电路的关键组成部分。 GP 活性失调与许多精神运动障碍有关，包括帕金森病 (PD)，其中病理生理学的一个主要特征是 GP 神经元放电模式和同步性的改变。然而，人们对 GP 神经元这种活动的决定因素知之甚少。为了帮助填补这一空白，我们使用电生理学、分子学和计算方法来识别和表征啮齿动物组织切片中的 GABA 能 GP 神经元。在体外，GABA能 GP 神经元产生规则的、自主的、单尖峰起搏器活动。超极化激活的环核苷酸门控阳离子 (HCN) 通道对此过程做出了重要贡献：用 ZD7288 阻断它们会显着减慢放电速率并降低其规律性。体细胞电压钳引起的HCN电流具有快速和慢速分量。单细胞 RT-PCR 和免疫组织化学方法揭示了 GABA 能 GP 神经元中 HCN2 亚基的强劲表达以及 HCN1 亚基的显着水平。纹状体 GABA 能输入 GP 神经元的瞬时激活导致依赖于 HCN 电流的节律放电重置。模拟表明，瞬时纹状体 GABA 能输入重置起搏的能力取决于树突 HCN2/HCN1 通道。总之，这些研究表明 GABA 能 GP 神经元中的 HCN 通道是起搏规律性和速率以及该活动的纹状体重置的关键决定因素，暗示 HCN 通道与 PD 同步性的出现有关。
The globus pallidus ( GP) is a critical component of the basal ganglia circuitry controlling motor behavior. Dysregulation of GP activity has been implicated in a number of psychomotor disorders, including Parkinson's disease (PD), in which a cardinal feature of the pathophysiology is an alteration in the pattern and synchrony of discharge in GP neurons. Yet the determinants of this activity in GP neurons are poorly understood. To help fill this gap, electrophysiological, molecular, and computational approaches were used to identify and characterize GABAergic GP neurons in tissue slices from rodents. In vitro, GABAergic GP neurons generate a regular, autonomous, single-spike pacemaker activity. Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels make an important contribution to this process: their blockade with ZD7288 significantly slowed discharge rate and decreased its regularity. HCN currents evoked by somatic voltage clamp had fast and slow components. Single-cell RT-PCR and immunohistochemical approaches revealed robust expression of HCN2 subunits as well as significant levels of HCN1 subunits in GABAergic GP neurons. Transient activation of striatal GABAergic input to GP neurons led to a resetting of rhythmic discharge that was dependent on HCN currents. Simulations suggested that the ability of transient striatal GABAergic input to reset pacemaking was dependent on dendritic HCN2/HCN1 channels. Together, these studies show that HCN channels in GABAergic GP neurons are key determinants of the regularity and rate of pacemaking as well as striatal resetting of this activity, implicating HCN channels in the emergence of synchrony in PD.