Homeostatic regulation of synaptic excitability: tonic GABA(A) receptor currents replace I(h) in cortical pyramidal neurons of HCN1 knock-out mice.
Homeostatic regulation of synaptic excitability: tonic GABA(A) receptor currents replace I(h) in cortical pyramidal neurons of HCN1 knock-out mice.
复制标题
DOI：
10.1523/jneurosci.3771-09.2010
复制
发表时间：
2010-02-17
期刊：
影响因子：
--
通讯作者：
Bayliss DA
中科院分区：
文献类型：
--
作者：
Chen X;Shu S;Schwartz LC;Sun C;Kapur J;Bayliss DA
兴奋性突触受体的动态调节常常介导了突触效应的动态平衡控制。在这里，我们报告了一种新的形式的动态平衡突触可塑性，其基础是控制树突信息传递的分流电流的调节。在野生型小鼠的皮质锥体神经元中，HCN1通道位于树突超极化激活的阳离子电流(Ih)之下，该电流用于限制突触输入的时间总和。在HCN1基因敲除的小鼠中，正如预期的那样，Ih在锥体神经元中减少，其对突触总和的影响明显减弱。出乎意料的是，我们在这些细胞中发现了显著增强的荷包牡丹碱-和L-655,708敏感的背景GAAA电流，这可能归因于选择性上调HCN1型基因敲除小鼠皮质中GAAAα5亚单位的表达。值得注意的是，尽管hh减少，但在hcn1基因敲除小鼠的锥体神经元中，诱发的EPSP的基线亚线性总和没有变化；然而，用荷包牡丹碱阻断紧张性GAAA电流对hcn1基因敲除小鼠锥体细胞的突触总和的促进作用强于野生型小鼠。在ih减少的情况下，使用计算或药理学方法，增加紧张性GABAA受体电导，恢复正常的基线突触总和，正如在hcn1基因敲除小鼠的神经元中观察到的那样。这些数据表明，上调α5亚单位介导的GABAA受体紧张性电流可以定量补偿Hcn1基因敲除小鼠皮质锥体神经元树突状ih的丢失，以维持正常的突触总和；这些数据进一步暗示，树突体突触效能是体内皮质神经元兴奋性的动态平衡调节的受控变量。
Homeostatic control of synaptic efficacy is often mediated by dynamic regulation of excitatory synaptic receptors. Here, we report a novel form of homeostatic synaptic plasticity based on regulation of shunt currents that control dendritosomatic information transfer. In cortical pyramidal neurons from wild type mice, HCN1 channels underlie a dendritic hyperpolarization-activated cationic current (Ih) that serves to limit temporal summation of synaptic inputs. In HCN1 knockout mice, as expected, Ih is reduced in pyramidal neurons and its effects on synaptic summation are strongly diminished. Unexpectedly, we found a markedly enhanced bicuculline- and L-655,708-sensitive background GABAA current in these cells that could be attributed to selective up-regulation of GABAA α5 subunit expression in the cortex of HCN1 knockout mice. Strikingly, despite diminished Ih, baseline sub-linear summation of evoked EPSPs was unchanged in pyramidal neurons from HCN1 knockout mice; however, blocking tonic GABAA currents with bicuculline enhanced synaptic summation more strongly in pyramidal cells from HCN1 knockout mice than in those cells from wild type mice. Increasing tonic GABAA receptor conductance in the context of reduced Ih, using computational or pharmacological approaches, restored normal baseline synaptic summation, as observed in neurons from HCN1 knockout mice. These data indicate that up-regulation of α5 subunit-mediated GABAA receptor tonic current compensates quantitatively for loss of dendritic Ih in cortical pyramidal neurons from HCN1 knockout mice to maintain normal synaptic summation; they further imply that dendritosomatic synaptic efficacy is a controlled variable for homeostatic regulation of cortical neuron excitability in vivo.