Mechanisms and implications of high depolarization baseline offsets in conductance-based neuronal models

Abstract

AbstractSomatic current-step injection is a routinely used protocol to characterize neurons and measure their electrophysiological properties. A signature feature of the responses of many neuronal types is an elevated baseline of action potential firing from the resting membrane potential, the depolarization baseline level offset (DBLO). We find that four key factors together account for high DBLO: Liquid Junction Potential correction, subthreshold impedance amplitude profile, fast potassium delayed rectifier kinetics, and appropriate transient sodium current kinetics. We show that simple mechanisms for DBLO, such as Ohmic depolarization due to current input, fail to explain the effect, and many sophisticated conductance-based models also do not correctly manifest DBLO. Neither low pass filtering effect of membrane nor high reversal potential of potassium channels are able to explain high DBLO. Using stochastic parameter search in conductance-based models of CA1 pyramidal neurons, we explore cellular morphology configurations and channel kinetics. Multi-compartment models which matched experimental subthreshold impedance amplitude profiles had higher DBLO than single compartment models. DBLO was further increased in models that exhibited rapid deactivation time-constants in the dominant potassium conductance. We also saw that certain transient sodium current kinetics resulted in higher DBLO than others. We emphasize that correct expression of DBLO in conductance-based models is important to make quantitative predictions about the levels of ion channels in a neuron and also to correctly predict mechanisms underlying cellular function, such as the role of persistent sodium in imparting firing bistability to a neuron.Abstract Figure