Preliminary Model: I-KCa Sensitivity
Although I-KCa functions primarily to repolarize the cell following action potential spikes, especially during bursts when intracellular Ca2+ accumulates due to the nonactivating I-CaHVA conductance, it also exerts an effect on subthreshold dynamics. As expected, decreasing the maximum I-KCa conductance in this model gradually decreased both the time of burst onset and the total number of spikes in the burst (figure 5a-i, ii). When I-KCa was turned off completely (gkbar=0), a short burst of two spikes was produced at an onset approximately 20% earlier than in the default model. These influences were graded, since a 50% decrease in I-KCa gkbar produced a burst of three spikes with an onset approximately 10% earlier than in the default model. Such a conductance decrease could be produced in vivo under conditions in which intracellular calcium accumulation was decreased, or under conditions of I-KCa channel down-regulation at a longer time scale.
Increasing the maximum conductance of I-KCa likewise shortened the burst, but via a different integrative role than was seen at decreasing conductance levels. Whereas low levels of this current result in gradual inactivation of fast voltage-gated Na+ channels (I-NaF) due to incomplete spike repolarization, high levels both delay burst onset and antagonize the regenerative I-NaP and I-NaR conductances responsible for burst continuation. Additionally, the delay of burst onset allows the noninactivating I-KM conductance to reach higher levels earlier in the burst. Setting I-KCa to 162.5% of the default gkbar produced a burst of three spikes with an onset approximately 20% later than in the default model, whereas an increase to 163% completely abolished the burst (figure 5a-iv). This result suggests that the relationship between spike number and I-KCa gkbar, although graded, is discontinuous. Such discontinuity seems to be a natural result of the manner in which neurons produce all-or-nothing action potentials from graded subthreshold voltage fluctuations.