Selective participation of somatodendritic HCN channels in inhibitory but not excitatory synaptic integration in neurons of the subthalamic nucleus.
Selective participation of somatodendritic HCN channels in inhibitory but not excitatory synaptic integration in neurons of the subthalamic nucleus.
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DOI：
10.1523/jneurosci.3898-10.2010
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发表时间：
2010-11-24
期刊：
影响因子：
--
通讯作者：
Bevan MD
中科院分区：
文献类型：
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作者：
Atherton JF;Kitano K;Baufreton J;Fan K;Wokosin D;Tkatch T;Shigemoto R;Surmeier DJ;Bevan MD
丘脑底核(STN)神经元的活动模式与运动功能和功能障碍密切相关，通过固有特性和抑制性和兴奋性突触输入的复杂相互作用而产生。在许多神经元中，超极化激活的环核苷酸门控(HCN)通道在正常状态和疾病状态下的内在兴奋性和突触整合中发挥着关键作用。然而，在强烈表达HCN通道的STN神经元中，它们的作用仍然相对不明。为了解决这一缺陷，我们将互补的分子和细胞电生理、成像和计算方法应用于大鼠的STN。分子图谱显示，单个STN神经元表达编码几个HCN亚基的mRNA，其中HCN_2和HCN_3最为丰富。光镜和电子显微镜分析表明，HCN_2亚基在体树突状细胞质膜上有较强的表达和分布。电压、电流和动态钳制分析、双光子钙成像和计算模型显示，HCN通道被GABAA受体介导的输入激活，从而限制了突触超极化和低电压激活的钙通道失活。尽管HCN通道也限制了通过双光子去除谷氨酸产生的EPSP的时间总和，但这一作用在很大程度上被HCN通道激活所必需的GABA能抑制所分流。综上所述，这些数据表明，STN神经元中的HCN通道可以选择性地对抗GABAA受体介导的苍白球抑制，从而促进单棘波活动，而不是反弹的爆发式放电。
The activity patterns of subthalamic nucleus (STN) neurons are intimately linked to motor function and dysfunction and arise through the complex interaction of intrinsic properties and inhibitory and excitatory synaptic inputs. In many neurons hyperpolarization-activated cyclic nucleotide gated (HCN) channels play key roles in intrinsic excitability and synaptic integration both under normal conditions and in disease states. However in STN neurons, which strongly express HCN channels, their roles remain relatively obscure. In order to address this deficit complementary molecular and cellular electrophysiological, imaging and computational approaches were applied to the rat STN. Molecular profiling demonstrated that individual STN neurons express mRNA encoding several HCN subunits, with HCN2 and 3 being the most abundant. Light and electron microscopic analysis showed that HCN2 subunits are strongly expressed and distributed throughout the somatodendritic plasma membrane. Voltage, current and dynamic clamp analysis, 2-photon Ca2+ imaging and computational modeling revealed that HCN channels are activated by GABAA receptor-mediated inputs and thus limit synaptic hyperpolarization and deinactivation of low voltage activated Ca2+ channels. Although HCN channels also limited the temporal summation of EPSPs, generated through 2-photon uncaging of glutamate, this action was largely shunted by GABAergic inhibition that was necessary for HCN channel activation. Together the data demonstrate that HCN channels in STN neurons are conformed to selectively counteract GABAA receptor-mediated inhibition arising from the globus pallidus and thus promote single spike activity rather than rebound burst firing.