Efficacy of synaptic inhibition depends on multiple, dynamically interacting mechanisms implicated in chloride homeostasis.
Efficacy of synaptic inhibition depends on multiple, dynamically interacting mechanisms implicated in chloride homeostasis.
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DOI：
10.1371/journal.pcbi.1002149
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发表时间：
2011-09
影响因子：
4.3
通讯作者：
De Koninck Y
中科院分区：
文献类型：
--
作者：
Doyon N;Prescott SA;Castonguay A;Godin AG;Kröger H;De Koninck Y
氯稳态是GABAA受体（GABAAR）介导的抑制作用强度和稳健性的关键决定因素。稳态Cl−梯度变化的影响相对容易理解，但Cl−流入、扩散、挤出和与其他离子相互作用之间的动态相互作用如何影响突触信号仍然不确定。在这里，我们使用电扩散模型来研究这些过程之间的非线性相互作用。结果表明，扩散是在快速时间尺度上重新分配细胞内Cl−负荷的关键，而Cl−挤出控制稳态水平。即使KCC 2均匀分布在整个细胞中，扩散和挤出之间的相互作用也会导致体-枝晶Cl−梯度。降低KCC 2活性导致GABAAR介导的抑制作用降低，但增加GABAAR输入无法完全补偿这种形式的去抑制作用，因为Cl−的活性依赖性积累。此外，如果尽管存在GABAAR输入但尖峰持续存在，则由于尖峰期间发生的大Cl−驱动力，Cl−积累变得加速。由此产生的正反馈回路导致了抑制的灾难性失败。模拟还揭示了其他反馈回路，例如Cl−和pH调节之间的竞争。几个模型的预测进行了测试，并证实了[Cl−]i成像实验。因此，我们的研究揭示了Cl−调节如何依赖于多种动态相互作用机制。此外，该模型表明，增强KCC 2活性超过正常水平不会对放电频率产生负面影响，也不会导致明显的细胞外K-积累，这表明增强KCC 2活性是治疗干预的有效策略。快速突触抑制依赖于氯电流使神经元兴奋或防止由同时兴奋性输入引起的去极化。这两种情况都必然涉及氯离子流入细胞，因此，细胞内氯离子浓度的变化。绝大多数模型忽略了离子浓度的变化，尽管实验证据表明这种变化会发生，而且并非无关紧要。有证据表明，几种神经系统疾病与氯离子排出能力不足有关，这提高了考虑氯离子稳态机制的重要性。在这些疾病状态下，稳态氯化物水平发生改变。快速氯化物动力学也可能受到影响，但这些变化还有待探索。为此，我们建立了一个电扩散模型，该模型跟踪氯离子和多种其他离子种类的浓度变化。在这个模型中的模拟揭示了许多复杂的，非线性的相互作用，具有重要的后果，突触抑制的功效。从模型的几个预测进行了测试，并证实了氯化物成像实验。
Chloride homeostasis is a critical determinant of the strength and robustness of inhibition mediated by GABAA receptors (GABAARs). The impact of changes in steady state Cl− gradient is relatively straightforward to understand, but how dynamic interplay between Cl− influx, diffusion, extrusion and interaction with other ion species affects synaptic signaling remains uncertain. Here we used electrodiffusion modeling to investigate the nonlinear interactions between these processes. Results demonstrate that diffusion is crucial for redistributing intracellular Cl− load on a fast time scale, whereas Cl−extrusion controls steady state levels. Interaction between diffusion and extrusion can result in a somato-dendritic Cl− gradient even when KCC2 is distributed uniformly across the cell. Reducing KCC2 activity led to decreased efficacy of GABAAR-mediated inhibition, but increasing GABAAR input failed to fully compensate for this form of disinhibition because of activity-dependent accumulation of Cl−. Furthermore, if spiking persisted despite the presence of GABAAR input, Cl− accumulation became accelerated because of the large Cl− driving force that occurs during spikes. The resulting positive feedback loop caused catastrophic failure of inhibition. Simulations also revealed other feedback loops, such as competition between Cl− and pH regulation. Several model predictions were tested and confirmed by [Cl−]i imaging experiments. Our study has thus uncovered how Cl− regulation depends on a multiplicity of dynamically interacting mechanisms. Furthermore, the model revealed that enhancing KCC2 activity beyond normal levels did not negatively impact firing frequency or cause overt extracellular K− accumulation, demonstrating that enhancing KCC2 activity is a valid strategy for therapeutic intervention. Fast synaptic inhibition relies on chloride current to hyperpolarize the neuron or to prevent depolarization caused by concurrent excitatory input. Both scenarios necessarily involve chloride flux into the cell and, thus, a change in intracellular chloride concentration. The vast majority of models neglect changes in ion concentration despite experimental evidence that such changes occur and are not inconsequential. The importance of considering chloride homeostasis mechanisms is heightened by evidence that several neurological diseases are associated with deficient chloride extrusion capacity. Steady state chloride levels are altered in those disease states. Fast chloride dynamics are also likely affected, but those changes have yet to be explored. To this end, we built an electrodiffusion model that tracks changes in the concentration of chloride plus multiple other ion species. Simulations in this model revealed a multitude of complex, nonlinear interactions that have important consequences for the efficacy of synaptic inhibition. Several predictions from the model were tested and confirmed with chloride imaging experiments.
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DOI：
10.1177/1073858408317955
发表时间：
2008-10
期刊：
The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
影响因子：
--
作者：
Fröhlich F;Bazhenov M;Iragui-Madoz V;Sejnowski TJ
通讯作者：
Sejnowski TJ
影响因子：
5.3
作者：
Cordero-Erausquin, M;Coull, JAM;De Koninck, Y
通讯作者：
De Koninck, Y
DOI：
10.1152/ajpheart.01216.2008
发表时间：
2009-04-01
影响因子：
4.8
作者：
Decker, Keith F.;Heijman, Jordi;Rudy, Yoram
通讯作者：
Rudy, Yoram
影响因子：
2.5
作者：
Clay, JR
通讯作者：
Clay, JR
影响因子：
2.9
作者：
Balena, Trevor;Acton, Brooke A.;Woodin, Melanie A.
通讯作者：
Woodin, Melanie A.