REVIEWS The action potential in mammalian central neurons Bruce P. Bean Abstract | The action potential of the squid giant axon is formed by just two voltage- dependent conductances in the cell membrane, yet mammalian central neurons typically express more than a dozen different types of voltage-dependent ion channels. This rich repertoire of channels allows neurons to encode information by generating action potentials with a wide range of shapes, frequencies and patterns. Recent work offers an increasingly detailed understanding of how the expression of particular channel types underlies the remarkably diverse firing behaviour of various types of neurons. Heterologous expression In the years since the Hodgkin–Huxley analysis of the components of voltage-dependent calcium currents, at 1 Expression of protein squid axon action potential , it has become clear that least 4 or 5 different components of voltage-activated molecules by the injection of most neurons contain far more than the two voltage- potassium current, at least 2 to 3 types of calcium-acti- complementary RNA into the dependent conductances found in the squid axon2,3. vated potassium currents, the hyperpolarization-acti- cytoplasm (or complementary Action potentials serve a very different function in neu- vated current I , and others. Because of this complexity, DNA into the nucleus) of host h cells that do not normally ronal cell bodies, where they encode information in their our understanding of how different conductances inter- express the proteins, such as frequency and pattern, than in axons, where they serve act to form the action potentials of even the best-studied Xenopus oocytes or primarily to rapidly propagate signals over distance. The central neurons is still incomplete, even though Hodgkin mammalian cell lines. membrane of the squid axon is a poor encoder, as it fires and Huxley devised the basic experimental approach still Spike only over a narrow range of frequencies when stimulated being used — voltage-clamp analysis of individual time- 4 Another term for an action by the injection of widely-varying current levels . By and voltage-dependent conductances and reconstruction potential (especially the contrast, most neuronal cell bodies (in both vertebrate of the whole by numerical modelling — more than half portion with the most rapidly and invertebrate animals) can fire over a far wider range a century ago1. In this review I discuss differences in changing voltage). of frequencies and can respond to small changes in input the shape, rate and pattern of firing of action potentials currents with significant changes in firing frequency5–10. between various types of neurons, focusing on mam- Clearly, this richer firing behaviour depends on the malian central neurons, and review recent advances in expression of more types of voltage-dependent ion chan- understanding the role of specific types of ion channels nels. Interestingly, although the squid axon is strikingly in generating these differences. deficient as an encoder, some other invertebrate axons can fire over a wide frequency range11 and have a richer All spikes are not alike repertoire of ion channel types12, as do at least some The shape of action potentials (BOX 1) differs consid- mammalian axons13. erably among various types of neurons in the mam- The presence of multiple channel types in most malian brain (FIG. 1). For example, in the cortex and neurons has been appreciated since at least the 1970s. hippocampus, GABA (γ-aminobutyric acid)-releasing However, few were prepared for the staggering number interneurons generally have narrower spikes than gluta- of distinct kinds of ion channels revealed over the last matergic pyramidal neurons. This is seen most clearly two decades by the convergent techniques of patch- in intracellular recordings, in which spike shape can be clamp recording, heterologous expression of cloned chan- determined precisely8,15,16 (FIG. 1), but the difference in Harvard Medical School, nels and genomic analysis — including, for example, spike width is also evident from extracellular record- 17 Department of Neurobiology, more than 100 principal subunits of potassium chan- ings in vivo . Cells with narrow spikes also commonly 220 Longwood Avenue, nels14. Even more surprising, perhaps, was the gradual (but not always8) display ‘fast-spiking’ behaviour: being Boston, Massachusetts realization of just how many distinct voltage-depend- capable of firing at high frequencies with little decrease 02115, USA. 5,6,8,9,15,18–20 e-mail: bruce_bean@hms. ent conductances are expressed by individual neurons in frequency during prolonged stimulation . harvard.edu in the mammalian brain — commonly including 2 Recently, the fast-spiking phenotype has been related to doi:10.1038/nrn2148 or 3 components of sodium current, 4 or 5 different expression of the Kv3 family of voltage-gated potassium NATURE REVIEWS | NEUROSCIENCE VOLUME 8 | JUNE 2007 | 451 © 2007 Nature Publishing Group REVIEWS Projection neurons Box 1 | Anatomy of an action potential Neurons with relatively long axons that project out of a The figure shows an action potential recorded from a Subthreshhold Suprathreshold local circuit (distinct from pyramidal neuron in the CA1 region of a rat current injection depolarizing current 117 interneurons). hippocampus , illustrating commonly measured parameters. The action potential was elicited by the Bursting Overshoot Repolarizing injection of just-suprathreshold depolarizing current The firing of a rapid series of phase (purple). Use of a brief (1 ms) injection has the advantage several action potentials with 0 mV that the spike and the afterpotentials are not directly very short (less than ~5 ms) Upstroke Spike height influenced by the current injection. The response to a interspike intervals. subthreshold current injection is also shown (red). Resting V Width 50% thresh potential (V ) is typically in the range of –85 mV to –60 mV Adaptation rest Slowing or cessation of firing Vrest in pyramidal neurons. Voltage threshold (Vthresh) is the most during a maintained stimulus. negative voltage that must be achieved by the current –62 mV injection for all-or-none firing to occur (in this neuron it is Initial segment 1 nA AHP about –53 mV, a typical value). Threshold is less well The slender initial region of an defined for spontaneously firing neurons, especially in axon where it originates from 1 ms isolated cell bodies where transition from gradual an axon hillock of the cell body interspike depolarization to spike is typically less abrupt (or sometimes from a major than in slice recordings, and for such cases threshold is more easily estimated from phase-plane plots (FIG. 2). The upstroke dendrite), characterized by the fasciculation of microtubules. (also called the depolarizing phase or rising phase) of the action potential typically reaches a maximum velocity at a voltage near 0 mV. Overshoot is defined as peak relative to 0 mV. Spike height is defined as the peak relative to either resting potential or (more commonly) the most negative voltage reached during the afterhyperpolarization (AHP) immediately after the spike. Spike width is most commonly measured as the width at half-maximal spike amplitude, as illustrated. This measurement is sometimes referred to, confusingly, as ‘half-width’ or ‘half-duration’; ‘half-height width’ would be clearer. As is typical for pyramidal neurons, the repolarizing phase (also called ‘falling phase’ or ‘downstroke’) has a much slower velocity than the rising phase. Figure modified, with permission, from REF. 117 © (1987) Cambridge Univ. Press. channels, the rapid and steeply voltage-dependent acti- presynaptic terminals can be quite different to that in vation and deactivation kinetics of which are well-suited the cell body of the same neuron39 (FIG. 1f,g). for generating narrow action potentials and short refrac- tory periods6,21–27. The fast-spiking phenotype is not con- Somatic versus membrane action potentials fined to interneurons, since Purkinje neurons (which are The Hodgkin–Huxley analysis of the squid axon action GABAergic projection neurons) also fire steadily at high potential1 was greatly facilitated by creating an artificial frequencies and have narrow action potentials that are situation in which all of the axonal membrane experi- repolarized mainly by Kv3-mediated currents28–31. Nor ences the same voltage at the same time — the ‘membrane are all fast-spiking neurons GABAergic, as neurons of action potential’ — which is achieved by inserting an axial the subthalamic nucleus, which are glutamatergic, have wire to make axial resistance negligible. In mammalian this phenotype7,32 and express large potassium currents neurons, action potentials are usually recorded from cell mediated by Kv3-family channels33. The calyx of Held, bodies in brain slices, in which axons and dendritic trees a presynaptic glutamatergic terminal, also has narrow are largely intact. In this situation, the cell body is roughly spikes with repolarization by Kv3 channels and can fire isopotential during the spike (that is, the membrane volt- at high frequencies34–36. age is the same at different places and undergoes simul- The distinctive phenotype of fast-spiking neurons taneous change), but there may be current flow between with narrow action potentials is unusual in that it the cell body and the dendrites and axon of the cell that presents a general correlation across many neuronal alters the shape of the action potential to some extent. types between firing behaviour and action potential In most central neurons, the spike appears to be initi- shape. In general, however, firing behaviour can take ated in the initial segment of the axon40–47, at a location many different forms of patterns and frequencies, with that in pyramidal neurons is typically 30–50 μm from little obvious correlation with spike shape8,15,37,38. The the cell body. This is far enough away that the shape firing pattern of a neuron (which includes frequency of the action potential recorded in the cell body can show of firing as a function of stimulus strength, bursting versus clear effects arising from non-uniformity of voltage40,41,47.