Although confirmation of the model’s predictions regarding the role of each included ionic conductance in the ELL granular cell will require extensive in vitro patch clamp work, there are several arguments that can be made concerning the plausibility of these predictions prior to such experimentation. Firstly, it is possible to estimate the maximum possible ionic conductances for each channel type in the granular cell by taking into account the known size and conductance of corresponding single channels, along with the estimated total surface area of the granular cell. Furthermore, maximum ionic conductances for each ion species were not changed more than 170% from values that are biologically realistic in rat cerebellar granule cells (figure III-3c). Secondly, as has already been mentioned, an argument can be made from homology with corresponding values from earlier work with rat cerebellar granule cells (D’Angelo et al., 2001). And lastly, emphasis of the model on relative ionic conductances, along with predictions concerning the interdependence of these relative conductances, makes the model’s predictions relatively invariant to considerations of absolute channel numbers.

The dependence of the models’ fit on the ratio between maximum I-NaP and I-KM conductances, as described by mapping of the corresponding I-NaP/I-KM parameter space onto granular cell spike number response for a range of input delays between 0 and 6ms (figures III-10, III-17, III-21), suggests the existence of cellular mechanisms for co-regulation of these two channel types. For example, a decrease in total I-NaP conductance, due to decreased gene transcription rates, post-transcriptional modification of channel subunits controlling activation kinetics, or alterations in channel trafficking and localization, could be expected to produce a corresponding down-regulation of total I-KM conductance within a relatively brief time window.

Testing of this hypothetical co-regulation could be done by comparing the effects of acute I-NaP/I-KM channel blockade in acute slice preparations with the effects of either chronic channel blockade in vitro or partial under-/over-expression of either channel in vivo. While sensitivity to acute channel blockade in vitro is expected to greatly attenuate the graded nature of the burst duration code in the granular cell, plausibility of this mechanism under realistically noisy biological conditions predicts gradual recovery of the burst duration code during either chronic channel blockade or manipulations influencing expression levels of either I-NaP or I-KM.

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