Srikanth Sunandha, Narayanan Rishikesh
Cellular Neurophysiology Laboratory, Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
Undergraduate Program, Indian Institute of Science, Bangalore, India.
Front Cell Neurosci. 2023 Oct 10;17:1241450. doi: 10.3389/fncel.2023.1241450. eCollection 2023.
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.
实现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做出反应？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，这些模型在接收θ频率输入时维持细胞自主钙稳态。在钙稳态时，我们从每个模型中单独删除11种活跃离子通道电导中的每一种。我们通过比较通道删除前后的内在电生理特性，测量了每次删除一种电导的急性影响。删除单个电导对生理特性（包括钙稳态）的急性影响是异质的，这取决于特性、特定模型和被删除的通道。离子通道与特性之间潜在的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（不包括被删除的电导）在θ频率活动期间朝着实现钙稳态的方向进化。当钙稳态因离子通道删除而受到干扰时，敲除后其他电导的可塑性确保了钙稳态对离子通道删除的恢复力。这些结果证明了钙稳态中的简并性，因为敲除模型中的钙稳态是在没有早期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、特性和被删除的通道），甚至在与被删除通道没有直接联系的特性中引入了变化。总之，旨在维持稳态的敲除后可塑性对几个通道和特性产生了异质的脱靶效应，这表明在解释涉及通道敲除的实验结果时应极其谨慎。
