PDF(Pubmed)
Abstract：
How do neurons that implement cell-autonomous self-regulation of calcium react to knockout of individual ion-channel conductances? To address this question, we used a heterogeneous population of 78 conductance-based models of hippocampal pyramidal neurons that maintained cell-autonomous calcium homeostasis while receiving theta-frequency inputs. At calcium steady-state, we individually deleted each of the 11 active ion-channel conductances from each model. We measured the acute impact of deleting each conductance (one at a time) by comparing intrinsic electrophysiological properties before and immediately after channel deletion. The acute impact of deleting individual conductances on physiological properties (including calcium homeostasis) was heterogeneous, depending on the property, the specific model, and the deleted channel. The underlying many-to-many mapping between ion channels and properties pointed to ion-channel degeneracy. Next, we allowed the other conductances (barring the deleted conductance) to evolve towards achieving calcium homeostasis during theta-frequency activity. When calcium homeostasis was perturbed by ion-channel deletion, post-knockout plasticity in other conductances ensured resilience of calcium homeostasis to ion-channel deletion. These results demonstrate degeneracy in calcium homeostasis, as calcium homeostasis in knockout models was implemented in the absence of a channel that was earlier involved in the homeostatic process. Importantly, in reacquiring homeostasis, ion-channel conductances and physiological properties underwent heterogenous plasticity (dependent on the model, the property, and the deleted channel), even introducing changes in properties that were not directly connected to the deleted channel. Together, post-knockout plasticity geared towards maintaining homeostasis introduced heterogenous off-target effects on several channels and properties, suggesting that extreme caution be exercised in interpreting experimental outcomes involving channel knockouts.
摘要：
实施钙的细胞自主自我调节的神经元如何对单个离子通道电导的敲除作出反应？为了解决这个问题，我们使用了78个基于电导的海马锥体神经元模型的异质群体，这些模型在接受theta频率输入的同时维持了细胞自主钙稳态。在钙稳态下，我们分别从每个模型中删除了11个活性离子通道电导。我们通过比较通道缺失之前和之后的固有电生理特性来测量删除每个电导（一次一个）的急性影响。删除个体电导对生理特性（包括钙稳态）的急性影响是异质的，根据属性，具体的模型,和删除的频道。离子通道和属性之间的潜在多对多映射指向离子通道简并性。接下来,我们允许其他电导（除非删除的电导）在theta频率活动期间朝着实现钙稳态的方向发展。当离子通道缺失扰乱钙稳态时，其他电导的敲除后可塑性确保了钙稳态对离子通道缺失的抵抗力。这些结果证明了钙稳态的简并性，因为基因敲除模型中的钙稳态是在没有较早参与稳态过程的通道的情况下实现的。重要的是,在重新获得稳态时，离子通道电导和生理特性经历了异质可塑性(取决于模型，财产,和删除的频道)，甚至在未直接连接到已删除通道的属性中引入更改。一起,基因敲除后可塑性旨在维持体内平衡，在几个通道和特性上引入了异质脱靶效应，这表明在解释涉及通道敲除的实验结果时应格外谨慎。
