Context and Complexity: How Ionic Conductances Interact to Control Neuronal Firing

Abstract

The action potential in the squid giant axon is generated by just two voltage-activated conductances, but mammalian neurons typically express well over a dozen different kinds of voltage-activated ion channels. Different types of neurons express different combinations of ion channels, with an especially high degree of diversity in the expression of potassium channels. How do particular combinations of ion channels interact to produce the variety of firing patterns seen in different kinds of neurons? This question can be addressed by a variety of experimental and computational approaches. Experimentally, the components of current flowing during action potentials can be “deconstructed” using the action potential clamp technique, in which a neuron is voltage clamped using its own trajectory of action potential firing as a command waveform and individual components of current are then defined by using selective pharmacological inhibitors. Two key lessons from analyzing how combinations of channels control firing patterns of mammalian neurons are: 1) Very small currents of 10's of pA flowing between spikes can powerfully influence spiking patterns. These currents often represent only a tiny open probability of the channel and may be hard to predict accurately by channel models formulated to fit much larger step-activated currents. 2) The influence of a particular channel type on firing can depend critically on the context of the other channels present. This is illustrated by several cases in which inhibiting particular voltage-dependent potassium channels has the paradoxical effect of slowing the rate of firing.