Action potential generation requires a high sodium channel density in the axon initial segment

The axon initial segment (AIS) is a specialized region in neurons where action potentials are initiated. It is commonly assumed that this process requires a high density of voltage-gated sodium (Na(+)) channels. Paradoxically, the results of patch-clamp studies suggest that the Na(+) channel density at the AIS is similar to that at the soma and proximal dendrites. Here we provide data obtained by antibody staining, whole-cell voltage-clamp and Na(+) imaging, together with modeling, which indicate that the Na(+) channel density at the AIS of cortical pyramidal neurons is approximately 50 times that in the proximal dendrites. Anchoring of Na(+) channels to the cytoskeleton can explain this discrepancy, as disruption of the actin cytoskeleton increased the Na(+) current measured in patches from the AIS. Computational models required a high Na(+) channel density (approximately 2,500 pS microm(-2)) at the AIS to account for observations on action potential generation and backpropagation. In conclusion, action potential generation requires a high Na(+) channel density at the AIS, which is maintained by tight anchoring to the actin cytoskeleton.     

Active dendrites support efficient initiation of dendritic spikes in hippocampal CA3 pyramidal neurons

CA3 pyramidal neurons are important for memory formation and pattern completion in the hippocampal network. It is generally thought that proximal synapses from the mossy fibers activate these neurons most efficiently, whereas distal inputs from the perforant path have a weaker modulatory influence. We used confocally targeted patch-clamp recording from dendrites and axons to map the activation of rat CA3 pyramidal neurons at the subcellular level. Our results reveal two distinct dendritic domains. In the proximal domain, action potentials initiated in the axon backpropagate actively with large amplitude and fast time course. In the distal domain, Na(+) channel-mediated dendritic spikes are efficiently initiated by waveforms mimicking synaptic events. CA3 pyramidal neuron dendrites showed a high Na(+)-to-K(+) conductance density ratio, providing ideal conditions for active backpropagation and dendritic spike initiation. Dendritic spikes may enhance the computational power of CA3 pyramidal neurons in the hippocampal network.     

Role of dendritic spines in action potential backpropagation: a numerical simulation study

Two remarkable aspects of pyramidal neurons are their complex dendritic morphologies and the abundant presence of spines, small structures that are the sites of excitatory input. Although the channel properties of the dendritic shaft membrane have been experimentally probed, the influence of spine properties in dendritic signaling and action potential propagation remains unclear. To explore this we have performed multi-compartmental numerical simulations investigating the degree of consistency between experimental data on dendritic channel densities and backpropagation behavior, as well as the necessity and degree of influence of excitable spines. Our results indicate that measured densities of Na(+) channels in dendritic shafts cannot support effective backpropagation observed in apical dendrites due to suprathreshold inactivation. We demonstrate as a potential solution that Na(+) channels in spines at higher densities than those measured in the dendritic shaft can support extensive backpropagation. In addition, clustering of Na(+) channels in spines appears to enhance their effect due to their unique morphology. Finally, we show that changes in spine morphology significantly influence backpropagation efficacy. These results suggest that, by clustering sodium channels, spines may serve to control backpropagation.     

Signal propagation in oblique dendrites of CA1 pyramidal cells

The electrophysiological properties of the oblique branches of CA1 pyramidal neurons are largely unknown and very difficult to investigate experimentally. These relatively thin dendrites make up the majority of the apical tree surface area and constitute the main target of Schaffer collateral axons from CA3. Their electrogenic properties might have an important role in defining the computational functions of CA1 neurons. It is thus important to determine if and to what extent the back- and forward propagation of action potentials (AP) in these dendrites could be modulated by local properties such as morphology or active conductances. In the first detailed study of signal propagation in the full extent of CA1 oblique dendrites, we used 27 reconstructed three-dimensional morphologies and different distributions of the A-type K(+) conductance (K(A)), to investigate their electrophysiological properties by computational modeling. We found that the local K(A) distribution had a major role in modulating action potential back propagation, whereas the forward propagation of dendritic spikes originating in the obliques was mainly affected by local morphological properties. In both cases, signal processing in any given oblique was effectively independent of the rest of the neuron and, by and large, of the distance from the soma. Moreover, the density of K(A) in oblique dendrites affected spike conduction in the main shaft. Thus the anatomical variability of CA1 pyramidal cells and their local distribution of voltage-gated channels may suit a powerful functional compartmentalization of the apical tree.     

High threshold, proximal initiation, and slow conduction velocity of action potentials in dentate granule neuron mossy fibers

Dentate granule neurons give rise to some of the smallest unmyelinated fibers in the mammalian CNS, the hippocampal mossy fibers. These neurons are also key regulators of physiological and pathophysiological information flow through the hippocampus. We took a comparative approach to studying mossy fiber action potential initiation and propagation in hippocampal slices from juvenile rats. Dentate granule neurons exhibited axonal action potential initiation significantly more proximal than CA3 pyramidal neurons. This conclusion was suggested by phase plot analysis of somatic action potentials and by local tetrodotoxin application to the axon and somatodendritic compartments. This conclusion was also verified by immunostaining for voltage-gated sodium channel alpha subunits and by direct dual soma/axonal recordings. Dentate neurons exhibited a significantly higher action potential threshold and slower axonal conduction velocity than CA3 neurons. We conclude that while the electrotonically proximal axon location of action potential initiation allows granule neurons to sensitively detect and integrate synaptic inputs, the neurons are sluggish to initiate and propagate an action potential.     

Dichotomy of action-potential backpropagation in CA1 pyramidal neuron dendrites.

In hippocampal CA1 pyramidal neurons, action potentials are typically initiated in the axon and backpropagate into the dendrites, shaping the integration of synaptic activity and influencing the induction of synaptic plasticity. Despite previous reports describing action-potential propagation in the proximal apical dendrites, the extent to which action potentials invade the distal dendrites of CA1 pyramidal neurons remains controversial. Using paired somatic and dendritic whole cell recordings, we find that in the dendrites proximal to 280 microm from the soma, single backpropagating action potentials exhibit <50% attenuation from their amplitude in the soma. However, in dendritic recordings distal to 300 microm from the soma, action potentials in most cells backpropagated either strongly (26-42% attenuation; n = 9/20) or weakly (71-87% attenuation; n = 10/20) with only one cell exhibiting an intermediate value (45% attenuation). In experiments combining dual somatic and dendritic whole cell recordings with calcium imaging, the amount of calcium influx triggered by backpropagating action potentials was correlated with the extent of action-potential invasion of the distal dendrites. Quantitative morphometric analyses revealed that the dichotomy in action-potential backpropagation occurred in the presence of only subtle differences in either the diameter of the primary apical dendrite or branching pattern. In addition, action-potential backpropagation was not dependent on a number of electrophysiological parameters (input resistance, resting potential, voltage sensitivity of dendritic spike amplitude). There was, however, a striking correlation of the shape of the action potential at the soma with its amplitude in the dendrite; larger, faster-rising, and narrower somatic action potentials exhibited more attenuation in the distal dendrites (300-410 microm from the soma). Simple compartmental models of CA1 pyramidal neurons revealed that a dichotomy in action-potential backpropagation could be generated in response to subtle manipulations of the distribution of either sodium or potassium channels in the dendrites. Backpropagation efficacy could also be influenced by local alterations in dendritic side branches, but these effects were highly sensitive to model parameters. Based on these findings, we hypothesize that the observed dichotomy in dendritic action-potential amplitude is conferred primarily by differences in the distribution, density, or modulatory state of voltage-gated channels along the somatodendritic axis.     

Ion channel properties underlying axonal action potential initiation in pyramidal neurons

A high density of Na+ channels in the axon hillock, or initial segment, is believed to determine the threshold for action potential initiation in neurons. Here we report evidence for an alternative mechanism that lowers the threshold in the axon. We investigated properties and distributions of ion channels in outside-out patches from axons and somata of layer 5 pyramidal neurons in rat neocortical slices. Na+ channels in axonal patches (<30 microm from the soma) were activated by 7 mV less depolarization than were somatic Na+ channels. A-type K+ channels, which were prominent in somatic and dendritic patches, were rarely seen in axonal patches. We incorporated these findings into numerical simulations which indicate that biophysical properties of axonal channels, rather than a high density of channels in the initial segment, are most likely to determine the lowest threshold for action potential initiation.     

Dendritic Na+ current inactivation can increase cell excitability by delaying a somatic depolarizing afterpotential

Many central neurons support active dendritic spike backpropagation mediated by voltage-gated currents. Active spikes in dendrites have been shown capable of providing feedback to the soma to influence somatic excitability and firing dynamics through a depolarizing afterpotential (DAP). In pyramidal cells of the electrosensory lobe of weakly electric fish, Na(+) spikes in dendrites undergo a frequency-dependent broadening that enhances the DAP to increase somatic firing frequency. We use a combination of dynamical analysis and electrophysiological recordings to demonstrate that spike broadening in dendrites is primarily caused by a cumulative inactivation of dendritic Na(+) current. We further show that a reduction in dendritic Na(+) current increases excitability by decreasing the interspike interval and promoting burst firing. This process arises when inactivation of dendritic Na(+) current shifts the latency of the dendritic spike to delay the arrival of the DAP sufficiently to increase its impact on somatic membrane potential despite a reduction in dendritic excitability. Furthermore, the relationship between dendritic Na(+) current density and somatic excitability is nonmonotonic, as intermediate levels of dendritic Na(+) current exert the greatest excitatory influence. These results reveal that temporal shifts in dendritic spike firing provide a novel means for backpropagating spikes to influence the final output of a cell.     

Dendritic voltage-gated ion channels regulate the action potential firing mode of hippocampal CA1 pyramidal neurons.

The role of dendritic voltage-gated ion channels in the generation of action potential bursting was investigated using whole cell patch-clamp recordings from the soma and dendrites of CA1 pyramidal neurons located in hippocampal slices of adult rats. Under control conditions somatic current injections evoked single action potentials that were associated with an afterhyperpolarization (AHP). After localized application of 4-aminopyridine (4-AP) to the distal apical dendritic arborization, the same current injections resulted in the generation of an afterdepolarization (ADP) and multiple action potentials. This burst firing was not observed after localized application of 4-AP to the soma/proximal dendrites. The dendritic 4-AP application allowed large-amplitude Na(+)-dependent action potentials, which were prolonged in duration, to backpropagate into the distal apical dendrites. No change in action potential backpropagation was seen with proximal 4-AP application. Both the ADP and action potential bursting could be inhibited by the bath application of nonspecific concentrations of divalent Ca(2+) channel blockers (NiCl and CdCl). Ca(2+) channel blockade also reduced the dendritic action potential duration without significantly affecting spike amplitude. Low concentrations of TTX (10-50 nM) also reduced the ability of the CA1 neurons to fire in the busting mode. This effect was found to be the result of an inhibition of backpropagating dendritic action potentials and could be overcome through the coordinated injection of transient, large-amplitude depolarizing current into the dendrite. Dendritic current injections were able to restore the burst firing mode (represented as a large ADP) even in the presence of high concentrations of TTX (300-500 microM). These data suggest the role of dendritic Na(+) channels in bursting is to allow somatic/axonal action potentials to backpropagate into the dendrites where they then activate dendritic Ca(2+) channels. Although it appears that most Ca(2+) channel subtypes are important in burst generation, blockade of T- and R-type Ca(2+) channels by NiCl (75 microM) inhibited action potential bursting to a greater extent than L-channel (10 microM nimodipine) or N-, P/Q-type (1 microM omega-conotoxin MVIIC) Ca(2+) channel blockade. This suggest that the Ni-sensitive voltage-gated Ca(2+) channels have the most important role in action potential burst generation. In summary, these data suggest that the activation of dendritic voltage-gated Ca(2+) channels, by large-amplitude backpropagating spikes, provides a prolonged inward current that is capable of generating an ADP and burst of multiple action potentials in the soma of CA1 pyramidal neurons. Dendritic voltage-gated ion channels profoundly regulate the processing and storage of incoming information in CA1 pyramidal neurons by modulating the action potential firing mode from single spiking to burst firing.     

Involvement of persistent Na+ current in spike initiation in primary sensory neurons of the rat mesencephalic trigeminal nucleus

It was recently shown that the persistent Na(+) current (I(NaP)) is generated in the proximal axon in response to somatic depolarization in neocortical pyramidal neurons, although the involvement of I(NaP) in spike initiation is still unclear. Here we show a potential role of I(NaP) in spike initiation of primary sensory neurons in the mesencephalic trigeminal nucleus (MTN) that display a backpropagation of the spike initiated in the stem axon toward the soma in response to soma depolarization. Riluzole (10 muM) and tetrodotoxin (TTX, 10 nM) caused an activation delay or a stepwise increase in the threshold for evoking soma spikes (S-spikes) without affecting the spike itself. Simultaneous patch-clamp recordings from the soma and axon hillock (AH) revealed that bath application of 50 nM TTX increased the delay in spike activation in response to soma depolarization, leaving the spike-backpropagation time from the AH to soma unchanged. This indicates that the increase in activation delay occurred in the stem axon. Furthermore, under a decreasing intracellular concentration gradient of QX-314 from the soma to AH created by QX-314-containing and QX-314-free patch pipettes, the amplitude and maximum rate of rise (MRR) of AH-spikes decreased with an increase in the activation delay following repetition of current-pulse injections, whereas S-spikes displayed decreases of considerably lesser degree in amplitude and MRR. This suggests that compared to S-spikes, AH-spikes more accurately reflect the attenuation of axonal spike by QX-314, consistent with the nature of spike backpropagation. These observations strongly suggest that low-voltage-activated I(NaP) is involved in spike initiation in the stem axon of MTN neurons.     

Multiple modes of action potential initiation and propagation in mitral cell primary dendrite

The mitral cell primary dendrite plays an important role in transmitting distal olfactory nerve input from olfactory glomerulus to the soma-axon initial segment. To understand how dendritic active properties are involved in this transmission, we have combined dual soma and dendritic patch recordings with computational modeling to analyze action-potential initiation and propagation in the primary dendrite. In response to depolarizing current injection or distal olfactory nerve input, fast Na(+) action potentials were recorded along the entire length of the primary dendritic trunk. With weak-to-moderate olfactory nerve input, an action potential was initiated near the soma and then back-propagated into the primary dendrite. As olfactory nerve input increased, the initiation site suddenly shifted to the distal primary dendrite. Multi-compartmental modeling indicated that this abrupt shift of the spike-initiation site reflected an independent thresholding mechanism in the distal dendrite. When strong olfactory nerve excitation was paired with strong inhibition to the mitral cell basal secondary dendrites, a small fast prepotential was recorded at the soma, which indicated that an action potential was initiated in the distal primary dendrite but failed to propagate to the soma. As the inhibition became weaker, a "double-spike" was often observed at the dendritic recording site, corresponding to a single action potential at the soma. Simulation demonstrated that, in the course of forward propagation of the first dendritic spike, the action potential suddenly jumps from the middle of the dendrite to the axonal spike-initiation site, leaving the proximal part of primary dendrite unexcited by this initial dendritic spike. As Na(+) conductances in the proximal dendrite are not activated, they become available to support the back-propagation of the evoked somatic action potential to produce the second dendritic spike. In summary, the balance of spatially distributed excitatory and inhibitory inputs can dynamically switch the mitral cell firing among four different modes: axo-somatic initiation with back-propagation, dendritic initiation either with no forward propagation, forward propagation alone, or forward propagation followed by back-propagation.     

Na(+) and K(+) concentrations, extra- and intracellular voltages, and the effect of TTX in hypoxic rat hippocampal slices

Severe hypoxia causes rapid depolarization of CA1 neurons and glial cells that resembles spreading depression (SD). In brain slices in vitro, the SD-like depolarization and the associated irreversible loss of function can be postponed, but not prevented, by blockade of Na(+) currents by tetrodotoxin (TTX). To investigate the role of Na(+) flux, we made recordings from the CA1 region in hippocampal slices in the presence and absence of TTX. We measured membrane changes in single CA1 pyramidal neurons simultaneously with extracellular DC potential (V(o)) and either extracellular [K(+)] or [Na(+)]; alternatively, we simultaneously recorded [Na(+)](o), [K(+)](o), and V(o). Confirming previous reports, early during hypoxia, before SD onset, [K(+)](o) began to rise, whereas [Na(+)](o) still remained normal and V(o) showed a slight, gradual, negative shift; neurons first hyperpolarized and then began to gradually depolarize. The SD-like abrupt negative DeltaV(o) corresponded to a near complete depolarization of pyramidal neurons and an 89% decrease in input resistance. [K(+)](o) increased by 47 mM and [Na(+)](o) dropped by 91 mM. Changes in intracellular Na(+) and K(+) concentrations, estimated on the basis of the measured extracellular ion levels and the relative volume fractions of the neuronal, glial, and extracellular compartment, were much more moderate. Because [Na(+)](o) dropped more than [K(+)](o) increased, simple exchange of Na(+) for K(+) cannot account for these ionic changes. The apparent imbalance of charge could be made up by Cl(-) influx into neurons paralleling Na(+) flux and release of Mg(2+) from cells. The hypoxia-induced changes in interneurons resembled those observed in pyramidal neurons. Astrocytes responded with an initial slow depolarization as [K(+)](o) rose. It was followed by a rapid but incomplete depolarization as soon as SD occurred, which could be accounted for by the reduced ratio, [K(+)](i)/[K(+)](o). TTX (1 microM) markedly postponed SD, but the SD-related changes in [K(+)](o) and [Na(+)](o) were only reduced by 23 and 12%, respectively. In TTX-treated pyramidal neurons, the delayed SD-like depolarization took off from a more positive level, but the final depolarized intracellular potential and input resistance were not different from control. We conclude that TTX-sensitive channels mediate only a fraction of the Na(+) influx, and that some of the K(+) is released in exchange for Na(+). Even though TTX-sensitive Na(+) currents are not essential for the self-regenerative membrane changes during hypoxic SD, in control solutions their activation may trigger the transition from gradual to rapid depolarization of neurons, thereby synchronizing the SD-like event.     

Distance-dependent modifiable threshold for action potential back-propagation in hippocampal dendrites

In hippocampal CA1 pyramidal neurons, action potentials generated in the axon back-propagate in a decremental fashion into the dendritic tree where they affect synaptic integration and synaptic plasticity. The amplitude of back-propagating action potentials (b-APs) is controlled by various biological factors, including membrane potential (Vm). We report that, at any dendritic location (x), the transition from weak (small-amplitude b-APs) to strong (large-amplitude b-APs) back-propagation occurs when Vm crosses a threshold potential, x. When Vm > x, back-propagation is strong (mostly active). Conversely, when Vm < x, back-propagation is weak (mostly passive). x varies linearly with the distance (x) from the soma. Close to the soma, x < resting membrane potential (RMP) and a strong hyperpolarization of the membrane is necessary to switch back-propagation from strong to weak. In the distal dendrites, x > RMP and a strong depolarization is necessary to switch back-propagation from weak to strong. At approximately 260 micrometer from the soma, 260 approximately RMP, suggesting that in this dendritic region back-propagation starts to switch from strong to weak. x depends on the availability or state of Na+ and K+ channels. Partial blockade or phosphorylation of K+ channels decreases x and thereby increases the portion of the dendritic tree experiencing strong back-propagation. Partial blockade or inactivation of Na+ channels has the opposite effect. We conclude that x is a parameter that captures the onset of the transition from weak to strong back-propagation. Its modification may alter dendritic function under physiological and pathological conditions by changing how far large action potentials back-propagate in the dendritic tree.     

Backpropagation of the delta oscillation and the retinal excitatory postsynaptic potential in a multi-compartment model of thalamocortical neurons

Uniform and non-uniform somato-dendritic distributions of the ion channels carrying the low-threshold Ca(2+) current (I(T)), the hyperpolarization-activated inward current (I(h)), the fast Na(+) current (I(Na)) and the delayed rectifier current (I(K)) were investigated in a multi-compartment model of a thalamocortical neuron for their suitability to reproduce the delta oscillation and the retinal excitatory post-synaptic potential recorded in vitro from the soma of thalamocortical neurons. The backpropagation of these simulated activities along the dendritic tree was also studied. A uniform somato-dendritic distribution of the maximal conductance of I(T) and I(K) (g(T) and g(K), respectively) was sufficient to simulate with acceptable accuracy: (i) the delta oscillation, and its phase resetting by somatically injected current pulses; as well as (ii) the retinal excitatory postsynaptic potential, and its alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate and/or N-methyl-D-aspartate components. In addition, simulations where the dendritic g(T) and g(K) were either reduced (both by up to 34%) or increased (both by up to 15%) of their respective value on the soma still admitted a successful reproduction of the experimental activity. When the dendritic distributions were non-uniform, models where the proximal and distal dendritic g(T) was up to 1.8- and 1. 2-fold larger, respectively, than g(T(s)) produced accurate simulations of the delta oscillation (and its phase resetting curves) as well as the synaptic potentials without need of a concomitant increase in proximal or distal dendritic g(K). Furthermore, an increase in proximal dendritic g(T) and g(K) of up to fourfold their respective value on the soma resulted in acceptable simulation results.Addition of dendritic Na(+) channels to the uniformly or non-uniformly distributed somato-dendritic T-type Ca(2+) and K(+) channels did not further improve the overall qualitative and quantitative accuracy of the simulations, except for increasing the number of action potentials in bursts elicited by low-threshold Ca(2+) potentials. Dendritic I(h) failed to produce a marked effect on the simulated delta oscillation and the excitatory postsynaptic potential.In the presence of uniform and non-uniform dendritic g(T) and g(K), the delta oscillation propagated from the soma to the distal dendrites with no change in frequency and voltage-dependence, though the dendritic action potential amplitude was gradually reduced towards the distal dendrites. The amplitude and rising time of the simulated retinal excitatory postsynaptic potential were only slightly decreased during their propagation from their proximal dendritic site of origin to the soma or the distal dendrites.These results indicate that a multi-compartment model with passive dendrites cannot fully reproduce the experimental activity of thalamocortical neurons, while both uniform and non-uniform somato-dendritic g(T) and g(K) distributions are compatible with the properties of the delta oscillation and the retinal excitatory postsynaptic potential recorded in vitro from the soma of these neurons. Furthermore, by predicting the existence of backpropagation of low-threshold Ca(2+) potentials and retinal postsynaptic potentials up to the distal dendrites, our findings suggest a putative role for the delta oscillation in the dendritic processing of neuronal activity, and support previous hypotheses on the interaction between retinal and cortical excitatory postsynaptic potentials on thalamocortical neuron dendrites.     

Weak action potential backpropagation is associated with high-frequency axonal firing capability in principal neurons of the gerbil medial superior olive

Principal neurons of the medial superior olive (MSO) convey azimuthal sound localization cues through modulation of their rate of action potential firing. Previous intracellular studies in vitro have shown that action potentials appear highly attenuated at the soma of MSO neurons, potentially reflecting specialized action potential initiation and/or a physically distant site of generation. To examine this more directly, we made dual patch-clamp recordings from MSO principal neurons in gerbil brainstem slices. Using somatic and dendritic whole-cell recordings, we show that graded action potentials at the soma are highly sensitive to the rate of rise of excitation and undergo strong attenuation in their backpropagation into the dendrites (length constant, 76 μm), particularly during strong dendritic excitation. Using paired somatic whole-cell and axonal loose-patch recordings, we show that action potentials recorded in the axon at distances > 25 μm are all-or-none, and uniform in amplitude even when action potentials appear graded at the soma. This proximal zone corresponded to the start of myelination in the axon, as assessed with immunocytochemical staining for myelin basic protein in single-labelled neurons. Finally, the axon was capable of sustaining remarkably high firing rates, with perfect entrainment occurring at frequencies of up to 1 kHz. Together, our findings show that action potential signalling in MSO principal neurons is highly secure, but shows a restricted invasion of the somatodendritic compartment of the cell. This restriction may be important for minimizing distortions in synaptic integration during the high frequencies of synaptic input encountered in the MSO.     

Propagation of action potentials in dendrites depends on dendritic morphology

Action potential propagation links information processing in different regions of the dendritic tree. To examine the contribution of dendritic morphology to the efficacy of propagation, simulations were performed in detailed reconstructions of eight different neuronal types. With identical complements of voltage-gated channels, different dendritic morphologies exhibit distinct patterns of propagation. Remarkably, the range of backpropagation efficacies observed experimentally can be reproduced by the variations in dendritic morphology alone. Dendritic geometry also determines the extent to which modulation of channel densities can affect propagation. Thus in Purkinje cells and dopamine neurons, backpropagation is relatively insensitive to changes in channel densities, whereas in pyramidal cells, backpropagation can be modulated over a wide range. We also demonstrate that forward propagation of dendritically initiated action potentials is influenced by morphology in a similar manner. We show that these functional consequences of the differences in dendritic geometries can be explained quantitatively using simple anatomical measures of dendritic branching patterns, which are captured in a reduced model of dendritic geometry. These findings indicate that differences in dendritic geometry act in concert with differences in voltage-gated channel density and kinetics to generate the diversity in dendritic action potential propagation observed between neurons. They also suggest that changes in dendritic geometry during development and plasticity will critically affect propagation. By determining the spatial pattern of action potential signaling, dendritic morphology thus helps to define the size and interdependence of functional compartments in the neuron.     

Characterization of Na+-activated K+ currents in larval lamprey spinal cord neurons

Potassium channels play an important role in controlling neuronal firing and synaptic interactions. Na(+)-activated K(+) (K(Na)) channels have been shown to exist in neurons in different regions of the CNS, but their physiological function has been difficult to assess. In this study, we have examined if neurons in the spinal cord possess K(Na) currents. We used whole cell recordings from isolated spinal cord neurons in lamprey. These neurons display two different K(Na) currents. The first was transient and activated by the Na(+) influx during the action potentials, and it was abolished when Na(+) channels were blocked by tetrodotoxin. The second K(Na) current was sustained and persisted in tetrodotoxin. Both K(Na) currents were abolished when Na(+) was substituted with choline or N-methyl-D-glucamine, indicating that they are indeed dependent on Na(+) influx into neurons. When Na(+) was substituted with Li(+), the amplitude of the inward current was unchanged, whereas the transient K(Na) current was reduced but not abolished. This suggests that the transient K(Na) current is partially activated by Li(+). These two K(Na) currents have different roles in controlling the action potential waveform. The transient K(Na) appears to act as a negative feedback mechanism sensing the Na(+) influx underlying the action potential and may thus be critical for setting the amplitude and duration of the action potential. The sustained K(Na) current has a slow kinetic of activation and may underlie the slow Ca(2+)-independent afterhyperpolarization mediated by repetitive firing in lamprey spinal cord neurons.     

Propagation of action potentials from the soma to individual dendrite of cultured rat amacrine cells is regulated by local GABA input

Retinal amacrine cells are interneurons that make lateral and vertical connections in the inner plexiform layer of the retina. Amacrine cells do not possess a long axon, and this morphological feature is the origin of their naming. Their dendrites function as both presynaptic and postsynaptic sites. Half of all amacrine cells are GABAergic inhibitory neurons that mediate lateral inhibition, and their light-evoked response consists of graded voltage changes and regenerative action potentials. There is evidence that the amount of neurotransmitter release from presynaptic sites is increased by spike propagation into the dendrite. Thus understanding of how action potentials propagate in dendrites is important to elucidating the extent and strength of lateral inhibition. In the present study, we used the dual whole cell patch-clamp technique on the soma and the dendrite of cultured rat amacrine cells and directly demonstrated that the action potentials propagate into the dendrites. The action potential in the dendrite was TTX sensitive and was affected by the local membrane potential of the dendrite. Propagation of the action potential was suppressed by local application of GABA to the dendrite. Dual dendrite whole cell patch-clamp recordings showed that GABA suppresses the propagation of action potentials in one dendrite of an amacrine cell, while the action potentials propagate in the other dendrites. It is likely that the action potentials in the dendrites are susceptible to various external factors resulting in the nonuniform propagation of the action potential from the soma of an amacrine cell.     

Beyond faithful conduction: short-term dynamics, neuromodulation, and long-term regulation of spike propagation in the axon

Most spiking neurons are divided into functional compartments: a dendritic input region, a soma, a site of action potential initiation, an axon trunk and its collaterals for propagation of action potentials, and distal arborizations and terminals carrying the output synapses. The axon trunk and lower order branches are probably the most neglected and are often assumed to do nothing more than faithfully conducting action potentials. Nevertheless, there are numerous reports of complex membrane properties in non-synaptic axonal regions, owing to the presence of a multitude of different ion channels. Many different types of sodium and potassium channels have been described in axons, as well as calcium transients and hyperpolarization-activated inward currents. The complex time- and voltage-dependence resulting from the properties of ion channels can lead to activity-dependent changes in spike shape and resting potential, affecting the temporal fidelity of spike conduction. Neural coding can be altered by activity-dependent changes in conduction velocity, spike failures, and ectopic spike initiation. This is true under normal physiological conditions, and relevant for a number of neuropathies that lead to abnormal excitability. In addition, a growing number of studies show that the axon trunk can express receptors to glutamate, GABA, acetylcholine or biogenic amines, changing the relative contribution of some channels to axonal excitability and therefore rendering the contribution of this compartment to neural coding conditional on the presence of neuromodulators. Long-term regulatory processes, both during development and in the context of activity-dependent plasticity may also affect axonal properties to an underappreciated extent.