Parameter search

Features and stimulation protocols included those to extract membrane resistance from voltage traces elicited by a 5pA depolarizing stimulus for a duration of 200ms. Rheobase was determined using a ramp protocol with a delay of 500 ms and current gradually increased from 0 to 1000pA over 1000msec, effectively with a slope of 1pA/ms.

A large proportion of models entered into the depolarization block. Although certain features are calculable, the results are not deemed accurate, and under further depolarization, not sustainable. Hence, additional feature constraints such as interspike interval coefficient of variation (ISI_CV) and firing rates were added. We conducted multiple checks so that the firing rate was also captured within the time window of the last 1000 ms.

To capture firing rate feature values (spikes/s), and in accordance with data from Planert et al. (2013), three separate protocols were used: firing rates at current injection equal to Rheobase, at Rheobase+50pA (FR50), and at Rheobase+100pA (FR100). In addition, ISI_CV within an interstimulus interval, after hyperpolarizing potential (AHP), action potential height (AP_height), time to first spike, or spike latency when elicited by Rheobase+50pA and Rheobase+100pA were each targeted as features constrained by the optimization algorithm. Two separate runs of optimizations were performed for WT and HD categories.

It was difficult to find PoMs spanning the complete feature ranges uniformly. We stopped the optimization when we achieved >1200 zero error models. The WT and HD firing rates were targeted to a mean value of 6 spikes/s and a target deviation of 4 spikes/s. In this way, the optimization algorithm would accept a model as a ‘good’ model if it had a firing rate between 2 and 10 spikes/s.