Persistence has its own reward: repetitive firing of action potentials in neurons

The problem seems trivial. Given a steady input (e.g. tonic synaptic activity), design a neuron to discharge repetitively for most or all of the duration of the input. The need for a solution to this problem is obvious. Without this ability, how can neurons relay the information delivered by a population of asynchronously firing afferents? On first inspection, the solution to this design problem appears to be obvious. Add a set of potassium channels that hyperpolarize the neuron after each action potential (i.e. the afterhyperpolarization). As this hyperpolarization gradually declines, the cell, and most importantly, the voltage-dependent sodium channels responsible for action potentials, will ‘see’ the decline in the hyperpolarization as a depolarization. Since these channels are activated by a depolarization, they are ideally suited to trigger another action potential. Problem solved! This simple solution may have a snag or two. The first hint of trouble can be found in reports of some neurons that fire only one action potential in response to a step of injected current. Single-spiking neurons form a distinct class of cells in both the dorsal and ventral horns (Ruscheweyh & Sandkuhler, 2002; Prescott & De Koninck, 2002). Given the design described above, it is not immediately obvious why some neurons would only fire one action potential. Do these cells have additional properties that actively prevent repetitive firing? Alternatively, what are they missing? The latter idea bears careful scrutiny given that some single-spiking neurons can be converted into repetitively firing cells with the application of serotonin (Garraway & Hochman, 2001). There is another snag. Biophysicists describe the operation of voltage-dependent sodium channels in terms of one open state and multiple closed and inactivated states (Taddese & Bean, 2002). In other words, their dependency on voltage is not simple. During slow depolarizations that are typical of the membrane potential trajectory between action potentials, sodium channels carrying a transient current responsible for action potentials will slip into an inactivated state. Now we have a second problem. The anticipated influx of sodium ions fails to materialize and the cell stops firing. In this issue of The Journal of Physiology, Theiss et al. (2007) provide an elegant answer to our design problem. Neurons in the ventral horn of the spinal cord can be divided into four distinct classes based on their response to a step of depolarizing current. Some fire repetitively for the entire duration of the current step; others discharge with a burst of action potentials at the start of the current step; some adopt a repetitive mode of firing or an initial burst response, depending on the input level; and finally, some fire only once – the ‘problem’ cells previously described. Voltage-clamp recordings from these cells revealed an intriguing pattern. In response to a slow voltage ramp that was designed to inactivate the sodium channels responsible for transient sodium currents, the cells that fired repetitively displayed a persistent sodium current that was activated at voltages hyperpolarized to the voltage threshold for action potentials. In contrast, this current was much smaller in initial burst and repetitive/burst cells, and absent in single-spiking cells. This persistent sodium current is just what we needed! As the cell slowly recovers from a postspike hyperpolarization, the persistent sodium current accelerates the depolarization and acts to limit inactivation of the transient sodium channels that generate the next action potential. If the cell lacks a persistent sodium current, single-spiking emerges. Correlations are well and good, but Theiss et al. (2007) go on to provide evidence of a causal link between persistent sodium currents and repetitive firing. In response to low concentrations of riluzole, the persistent sodium current is greatly reduced. This reduction transforms all three classes of repetitively firing neurons into single-spiking cells. Importantly, these cells retain the ability to fire multiple action potentials, but only if they are stimulated with repeated short current pulses. This study is significant for several reasons. In addition to other important roles (Vervaeke et al. 2006), persistent sodium currents may also ensure a repetitive discharge in response to tonic synaptic activity. In turn, this helps to shape the unique firing patterns of different classes of cells (see also Kuo et al. 2006). It is also significant that ventral horn interneurons are endowed with these channels. These cells relay descending and segmental signals to motoneurons. Thus, this relay may be subject to dynamic transformations based on the state of the channels responsible for persistent sodium currents. If the behaviour of these channels is altered, as might happen after spinal cord injury (Harvey et al. 2006), the signals reaching motoneurons may be changed in ways that could facilitate or impede recovery.

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