Inactivating ion channels augment robustness of subthreshold intrinsic response dynamics to parametric variability in hippocampal model neurons
Authors: Rathour Rahul Kumar , Narayanan Rishikesh 
Published: August 2012

Key points
Voltage‐gated ion channels (VGICs) play a critical role in determining how neurons respond to oscillatory inputs at various frequencies. How do inactivating VGICs regulate neuronal response properties to oscillatory inputs?
T‐type Ca2+ channels mediate resonance in response to oscillatory inputs, without being accompanied by a lead in the intrinsic phase response, and A‐type K+ channels act analogous to a leak channel with reference to many measurements characterizing intrinsic response dynamics (IRD).
Coexpression of these channels with a hyperpolarization‐activated h channel augmented the range of parameters over which they sustained resonance and phase lead.
Global sensitivity analysis demonstrates that functionally similar models could be achieved even when underlying parameters displayed tremendous variability and exhibited weak pair‐wise correlations.
A simplistic one‐parameter‐a‐time analysis that does not account for the complex and non‐linear interactions between channels would fail to provide a full understanding of subthreshold IRD.
Abstract  Voltage‐gated ion channels play a critical role in regulating neuronal intrinsic response dynamics (IRD). Here, we computationally analysed the roles of the two inactivating subthreshold conductances (A and T), individually and in various combinations with the non‐inactivating h conductance, in regulating several physiological IRD measurements in the theta frequency range. We found that the independent presence of a T conductance, unlike that of an h conductance, was unable to sustain an inductive phase lead in the theta frequency range, despite its ability to mediate theta frequency resonance. The A conductance, on the other hand, when expressed independently, acted in a manner similar to a leak conductance with reference to most IRD measurements. Next, analysing the impact of pair‐wise coexpression of these channels, we found that the coexpression of the h and T conductances augmented the range of parameters over which they sustained resonance and inductive phase lead. Additionally, coexpression of the A conductance with the h or the T conductance elicited changes in IRD measurements that were similar to those obtained with the expression of a leak conductance with a resonating conductance. Finally, to understand the global sensitivity of IRD measurements to all parameters associated with models expressing all three channels, we generated 100,000 neuronal models, each built with a unique set of parametric values. We categorized valid models among these by matching their IRD measurements with experimental counterparts, and found that functionally similar models could be achieved even when underlying parameters displayed tremendous variability and exhibited weak pair‐wise correlations. Our results suggest that the three prominent subthreshold conductances contribute differently to intrinsic excitability and to phase coding. We postulate that the differential expression and activity‐dependent plasticity of these conductances contribute to robustness of subthreshold IRD, whereby response homeostasis is achieved by recruiting several non‐unique combinations of these channel parameters.