A re-excitation mechanism for strychnine-induced doublets in molluscan neurons

The effects of strychnine on Aplysia R2 neurons were evaluated using simultaneous intracellular recordings of the soma and axon potentials. 1 mM strychnine produced a slight enlargement of the somatic spike and a large increase of the axon spike duration. Following direct stimulation, the soma displayed depolarizing afterpotentials ( DAPs ) which might trigger extra-spikes, both produced electronically by long-lasting axon spikes. Cobalt suppressed both the axon spike lengthening and the somatic extra-spikes or DAPs , and induced large depolarizing shifts in the soma. The region of largest spike lengthening (proximal axon) had a large density of Ca channels. The different effects of strychnine on the soma and on the axon were assumed to result from a selective blockage of the V-dependent K channels which would predominate in the axon whereas Ca-activated K channels would predominate in the soma.     

Role of A-type K+ channels in spike broadening observed in soma and axon of Hermissenda type-B photoreceptors: A simulation study

In Hermissenda type-B photoreceptors, the spike is generated in the axon and back-propagated to the soma, resulting in smaller somatic spikes. Experimentally, blocking the A-type K⁺ current (I_K,A) results in broadening of somatic spikes. Similarly, in a compartmental model of the photoreceptor, reducing the maximum A-type K⁺ conductance (g_K,Amax) results in broadening of somatic spikes. However, simulations predict that little or no broadening of axonal spikes occurs when g_K,Amax is reduced. The results can be explained by the voltage-dependent properties of I_K,A and the different potential ranges that the somatic and axonal spike traverse. Because of the steeper I-V curve and faster activation of the K⁺ channels at higher potentials, the recruitment of additional K⁺ channels in the axon is able to compensate for the decrease in K⁺ conductance, yielding less spike broadening. These results also support the idea that spike duration in the axon may not be reliably inferred based upon recordings collected from the soma. Action Editor: Jonathan D. Victor     

Excitability of the soma in central nervous system neurons

The ability of the soma of a spinal dorsal horn neuron, a spinal ventral horn neuron (presumably a motoneuron), and a hippocampal pyramidal neuron to generate action potentials was studied using patch-clamp recordings from rat spinal cord slices, the "entire soma isolation" method, and computer simulations. By comparing original recordings from an isolated soma of a dorsal horn neuron with simulated responses, it was shown that computer models can be adequate for the study of somatic excitability. The modeled somata of both spinal neurons were unable to generate action potentials, showing only passive and local responses to current injections. A four- to eightfold increase in the original density of Na(+) channels was necessary to make the modeled somata of both spinal neurons excitable. In contrast to spinal neurons, the modeled soma of the hippocampal pyramidal neuron generated spikes with an overshoot of +9 mV. It is concluded that the somata of spinal neurons cannot generate action potentials and seem to resist their propagation from the axon to dendrites. In contrast, the soma of the hippocampal pyramidal neuron is able to generate spikes. It cannot initiate action potentials in the intact neurons, but it can support their back-propagation from the axon initial segment to dendrites.     

Axons Amplify Somatic Incomplete Spikes into Uniform Amplitudes in Mouse Cortical Pyramidal Neurons

Background

Action potentials are the essential unit of neuronal encoding. Somatic sequential spikes in the central nervous system appear various in amplitudes. To be effective neuronal codes, these spikes should be propagated to axonal terminals where they activate the synapses and drive postsynaptic neurons. It remains unclear whether these effective neuronal codes are based on spike timing orders and/or amplitudes.

Methodology/Principal Findings

We investigated this fundamental issue by simultaneously recording the axon versus soma of identical neurons and presynaptic vs. postsynaptic neurons in the cortical slices. The axons enable somatic spikes in low amplitude be enlarged, which activate synaptic transmission in consistent patterns. This facilitation in the propagation of sequential spikes through the axons is mechanistically founded by the short refractory periods, large currents and high opening probability of axonal voltage-gated sodium channels.

Conclusion/Significance

An amplification of somatic incomplete spikes into axonal complete ones makes sequential spikes to activate consistent synaptic transmission. Therefore, neuronal encoding is likely based on spike timing order, instead of graded analogues.     

Location-dependent effects of inhibition on local spiking in pyramidal neuron dendrites

Cortical computations are critically dependent on interactions between pyramidal neurons (PNs) and a menagerie of inhibitory interneuron types. A key feature distinguishing interneuron types is the spatial distribution of their synaptic contacts onto PNs, but the location-dependent effects of inhibition are mostly unknown, especially under conditions involving active dendritic responses. We studied the effect of somatic vs. dendritic inhibition on local spike generation in basal dendrites of layer 5 PNs both in neocortical slices and in simple and detailed compartmental models, with equivalent results: somatic inhibition divisively suppressed the amplitude of dendritic spikes recorded at the soma while minimally affecting dendritic spike thresholds. In contrast, distal dendritic inhibition raised dendritic spike thresholds while minimally affecting their amplitudes. On-the-path dendritic inhibition modulated both the gain and threshold of dendritic spikes depending on its distance from the spike initiation zone. Our findings suggest that cortical circuits could assign different mixtures of gain vs. threshold inhibition to different neural pathways, and thus tailor their local computations, by managing their relative activation of soma- vs. dendrite-targeting interneurons.     

A prolonged,voltage-dependent calcium permeability revealed by tetraethylammonium in the soma and axon of Aplysia giant neuron

The soma but not the axon of the giant neuron, R2, of Aplysia can generate an all-or-none Ca spike in Na-free or TTX-containing medium (Junge and Miller, 1974). Extracellular axonal recordings made at several distances from the soma provide evidence that the transition in ability to fire a spike in Na-free medium occurs within the first 250 μm of the axon. Application of 25 mM TEA-Br to the bathing medium causes a more than tenfold increase in the duration of the somatic action potential. The duration of the axonal action potential in TEA decreases with distance from the soma. At distances greater than 3 mm from the soma this concentration of TEA causes little or no increase in the duration of the axon spike. The effect of 25 mM TEA on both the soma and proximal axon is blocked reversibly by 30 mM CoCl₂ or 1 mM CdCl₂. The duration of the somatic action potential in TEA increases with an increase in Ca concentration of the bath. At a constant concentration of Na, the voltage level of the somatic plateau increases with Ca concentration in the manner predicted for a Ca electrode. In the presence of 11 mM Ca²⁺ the potential of the plateau is relatively insensitive to Na concentration. The TEA plateau in R2 reveals a prolonged voltage-dependent permeability to Ca. The duration of the plateau may indicate the degree of Ca activation during a spike.     

Axonal contribution to subthreshold currents inaplysia bursting pacemaker neurons

The contribution of axonal activity to the ionic currents which generate bursting pacemaker activity was studied by using the two-electrode voltage-clamp technique in Aplysia bursting neuron somata in conjunction with intraaxonal voltage recordings. Depolarizing voltage-clamp pulses applied to bursting cell somata triggered axonal action potentials. The voltage-clamp current recording exhibited transient inward current "notches" corresponding to each of the axonal spikes. The addition of 50 microM tetrodotoxin (TTX) to the bathing medium blocked the fast axonal spikes and current notches, revealing a slower axonal spike which was blocked by the replacement of external Ca2+ with Co2+. The inward current evoked by applying a depolarizing voltage-clamp pulse in the soma is distorted by the occurrence of the axonal Ca2+ spike. Elimination of the axonal spike, by injecting hyperpolarizing current into the axon, changes both the time course and the magnitude of the inward current. The axonal Ca2+ spikes are followed by a series of Ca2+-dependent afterpotentials: a rapid postspike hyperpolarization, a depolarizing afterpotential (DAP) and, finally, a long-lasting postburst hyperpolarization. The long-lasting hyperpolarization is not blocked by 50 mM external tetraethyl ammonium, an effective blocker of Ca2+-activated K+ current [IK(Ca)], and does not appear to reverse at EK. Hence, the axonal long-lasting hyperpolarization may not be due to IK(Ca). Somatic voltage-clamp pulses in bursting neurons are followed by a slow inward tail current, which is sometimes coincident with a DAP in the axon. In some cells, the amplitude of the slow inward tail current is greatly reduced if axonal spikes and DAPs are prevented by hyperpolarization of the axon, while, in other cells, elimination of axonal activity has little effect. Therefore, the slow inward tail current is not necessarily an artifact of poor voltage-clamp control over the axonal membrane potential but probably results from the activation of an ionic conductance mechanism located partly in the axon and partly in the soma.     

Action potential generation by turtle cortical neurons. Dendritic and somatic spikes

Action potentials of neurons of the turtle general cortex and the pattern of their generation were studied by an intracellular recording method. Besides the complete action potential, the cells also generate partial spikes of varied amplitude which compose the complete action potential. The threshold of generation and the discrete amplitude of each partial spike are not strictly constant but they fluctuate gradually and spontaneously within certain limits without any change in membrane potential of the cell. Somatic and dendritic spikes are distinguished. The trigger zones of the latter are located at various distances from the soma. During orthodromic activation of cortical neurons dendritic spikes are generated consecutively and spread to the some electrotonically with a decrement. They are the immediate cause of generation of the somatic spike.M. V. Lomonovsov Moscow State University. Translated from Neirofiziologiya, Vol. 8, No. 3, pp. 237–242, May–June, 1976.     

Extra spike formation in sensory neurons and the disruption of afferent spike patterning

The peculiar pseudounipolar geometry of primary sensory neurons can lead to ectopic generation of "extra spikes" in the region of the dorsal root ganglion potentially disrupting the fidelity of afferent signaling. We have used an explicit model of myelinated vertebrate sensory neurons to investigate the location and mechanism of extra spike formation, and its consequences for distortion of afferent impulse patterning. Extra spikes originate in the initial segment axon under conditions in which the soma spike becomes delayed and broadened. The broadened soma spike then re-excites membrane it has just passed over, initiating an extra spike which propagates outwards into the main conducting axon. Extra spike formation depends on cell geometry, electrical excitability, and the recent history of impulse activity. Extra spikes add to the impulse barrage traveling toward the spinal cord, but they also travel antidromically in the peripheral nerve colliding with and occluding normal orthodromic spikes. As a result there is no net increase in afferent spike number. However, extra spikes render firing more staccato by increasing the number of short and long interspike intervals in the train at the expense of intermediate intervals. There may also be more complex changes in the pattern of afferent spike trains, and hence in afferent signaling.     

Presynaptic action potential amplification by voltage-gated Na+ channels in hippocampal mossy fiber boutons

Action potentials in central neurons are initiated near the axon initial segment, propagate into the axon, and finally invade the presynaptic terminals, where they trigger transmitter release. Voltage-gated Na(+) channels are key determinants of excitability, but Na(+) channel density and properties in axons and presynaptic terminals of cortical neurons have not been examined yet. In hippocampal mossy fiber boutons, which emerge from parent axons en passant, Na(+) channels are very abundant, with an estimated number of approximately 2000 channels per bouton. Presynaptic Na(+) channels show faster inactivation kinetics than somatic channels, suggesting differences between subcellular compartments of the same cell. Computational analysis of action potential propagation in axon-multibouton structures reveals that Na(+) channels in boutons preferentially amplify the presynaptic action potential and enhance Ca(2+) inflow, whereas Na(+) channels in axons control the reliability and speed of propagation. Thus, presynaptic and axonal Na(+) channels contribute differentially to mossy fiber synaptic transmission.     

First node of Ranvier facilitates high-frequency burst encoding

In central neurons the first node of Ranvier is located at the first axonal branchpoint, ～ 100 μm from the axon initial segment where synaptic inputs are integrated and converted into action potentials (APs). Whether the first node contributes to this signal transformation is not well understood. Here it was found that in neocortical layer 5 axons, the first branchpoint is required for intrinsic high-frequency (≥ 100 Hz) AP bursts. Furthermore, block of nodal Na(+) channels or axotomy of the first node in intrinsically bursting neurons depolarized the somatic AP voltage threshold (～ 5 mV) and eliminated APs selectively within a high-frequency cluster in response to steady currents or simulated synaptic inputs. These results indicate that nodal persistent Na(+) current exerts an anterograde influence on AP initiation in the axon initial segment, revealing a computational role of the first node of Ranvier beyond conduction of the propagating AP.     

Amplitude-dependent spike-broadening and enhanced Ca(2+) signaling in GnRH-secreting neurons

In GnRH-secreting (GT1) neurons, activation of Ca(2+)-mobilizing receptors induces a sustained membrane depolarization that shifts the profile of the action potential (AP) waveform from sharp, high-amplitude to broad, low-amplitude spikes. Here we characterize this shift in the firing pattern and its impact on Ca(2+) influx experimentally by using prerecorded sharp and broad APs as the voltage-clamp command pulse. As a quantitative test of the experimental data, a mathematical model based on the membrane and ionic current properties of GT1 neurons was also used. Both experimental and modeling results indicated that inactivation of the tetrodotoxin-sensitive Na(+) channels by sustained depolarization accounted for a reduction in the amplitude of the spike upstroke. The ensuing decrease in tetraethylammonium-sensitive K(+) current activation slowed membrane repolarization, leading to AP broadening. This change in firing pattern increased the total L-type Ca(2+) current and facilitated AP-driven Ca(2+) entry. The leftward shift in the current-voltage relation of the L-type Ca(2+) channels expressed in GT1 cells allowed the depolarization-induced AP broadening to facilitate Ca(2+) entry despite a decrease in spike amplitude. Thus the gating properties of the L-type Ca(2+) channels expressed in GT1 neurons are suitable for promoting AP-driven Ca(2+) influx in receptor- and non-receptor-depolarized cells.     

Modes of Initiation and Propagation of Spikes in the Branching Axons of Molluscan Central Neurons

A study has been made of Aplysia nerve cells, mainly in the pleural ganglia, in which the main axon divides into at least two branches in the neighbourhood of the soma. Conduction between these branches was investigated by intracellular recordings from the soma following antidromic stimulation via the nerves containing the axonal branches. It has been shown that transmission between separate branches need not involve discharge of the soma but only of the axonal region between the soma and the origin of the branches. In some cells, the spike may fail to invade the other axonal branch, whereas transmission in the opposite direction is readily achieved. Often spikes in none of the branches are transmitted to the others, unless facilitated. Indications about the geometry of the neuron in the vicinity of the soma may be obtained from the study of the relative size of the A spikes originated in different branches. These observations, together with the presence of different sizes of A spikes, produced by orthodromic stimulation, provide evidence that spikes initiated at separate axonal "trigger zones" of Aplysia neurons may be conducted selectively to the effectors or other neurons innervated by the particular branch.     

Local field potential modeling predicts dense activation in cerebellar granule cells clusters under LTP and LTD control

Local field-potentials (LFPs) are generated by neuronal ensembles and contain information about the activity of single neurons. Here, the LFPs of the cerebellar granular layer and their changes during long-term synaptic plasticity (LTP and LTD) were recorded in response to punctate facial stimulation in the rat in vivo. The LFP comprised a trigeminal (T) and a cortical (C) wave. T and C, which derived from independent granule cell clusters, co-varied during LTP and LTD. To extract information about the underlying cellular activities, the LFP was reconstructed using a repetitive convolution (ReConv) of the extracellular potential generated by a detailed multicompartmental model of the granule cell. The mossy fiber input patterns were determined using a Blind Source Separation (BSS) algorithm. The major component of the LFP was generated by the granule cell spike Na(+) current, which caused a powerful sink in the axon initial segment with the source located in the soma and dendrites. Reproducing the LFP changes observed during LTP and LTD required modifications in both release probability and intrinsic excitability at the mossy fiber-granule cells relay. Synaptic plasticity and Golgi cell feed-forward inhibition proved critical for controlling the percentage of active granule cells, which was 11% in standard conditions but ranged from 3% during LTD to 21% during LTP and raised over 50% when inhibition was reduced. The emerging picture is that of independent (but neighboring) trigeminal and cortical channels, in which synaptic plasticity and feed-forward inhibition effectively regulate the number of discharging granule cells and emitted spikes generating "dense" activity clusters in the cerebellar granular layer.     

Afterhyperpolarization improves spike programming through lowering threshold potentials and refractory periods mediated by voltage-gated sodium channels

Neurons program various patterns of sequential spikes as neural codes to guide animal behavior. Studies show that spike programming (capacity and timing precision) is influenced by inhibitory synaptic inputs and membrane afterhyperpolarization (AHP). Less is clear about how these inhibitory components regulate spike programming, which we investigated at the cortical neurons. Whole-cell current-clamp recording for action potentials and single channel recording for voltage-gated sodium channels (VGSC) were conducted at regular-spiking and fast-spiking neurons in the cortical slices. With quantifying the threshold potentials and refractory periods of sequential spikes, we found that fast-spiking neurons expressing AHP possess lower threshold potentials and shorter refractory periods, and the hyperpolarization pulse immediately after each of spikes lowers threshold potentials and shortens refractory periods at regular-spiking neurons. Moreover, the hyperpolarization pulses shorten the refractory periods for VGSC reactivation and threshold potentials for its sequential activation. Our data indicate that inhibitory components immediately after spikes, such as AHP and recurrent inhibition, improve spike capacity and timing precision via lowering the refractory periods and threshold potentials mediated by voltage-gated sodium channels.     

Steps in the production of motoneuron spikes

1. Spikes evoked in spinal motoneurons by antidromic stimulation normally present an inflection in their rising phase. A similar inflection is present in spikes evoked by direct stimulation with short pulses. 2. In either case the inflection becomes less prominent if the motoneuron membrane is depolarized and more prominent when it is hyperpolarized. Both antidromic and direct spikes may fall from the level of the inflection thus evoking a "small spike" only if sufficient hyperpolarization is applied. Similar events occur when antidromic or direct spikes are evoked in the aftermath of a preceding spike. 3. Spikes evoked by direct stimuli applied shortly after firing of a "small spike" may also become partially blocked at a critical stimulus interval. At shorter intervals, however, spike size again increases and no inflection can be detected in the rising phase. 4. When a weak direct stimulus evokes a small spike only, a stronger stimulus may evoke a full spike. Curves of the strength of the stimuli required for eliciting small or full spikes have been constructed in a number of conditions. 5. To explain the results it is assumed that threshold of the major portions of the soma membrane is higher than the threshold of the axon, the transition occurring over a finite area near the axon hillock. Following antidromic or direct stimulation, soma excitation is then initiated in the region of the axon hillock. Spread of activity towards the soma occurs at first slowly and with low safety factor. At this stage block may be easily evoked. Safety factor for propagation increases rapidly as the growing impulse involves larger and larger areas of the soma membrane so that, once the critical areas are excited, activation of the remaining portions of the soma membrane will suddenly occur.     

Oscillatory burst discharge generated through conditional backpropagation of dendritic spikes.

Gamma frequencies of burst discharge (>40 Hz) have become recognized in select cortical and non-cortical regions as being important in feature extraction, neural synchrony and oscillatory discharge. Pyramidal cells of the electrosensory lateral line lobe (ELL) of Apteronotus leptorhynchus generate burst discharge in relation to specific features of sensory input in vivo that resemble those recognized as gamma frequency discharge when examined in vitro. We have shown that these bursts are generated by an entirely novel mechanism termed conditional backpropagation that involves an intermittent failure of dendritic Na+ spike conduction. Conditional backpropagation arises from a frequency-dependent broadening of dendritic spikes during repetitive discharge, and a mismatch between the refractory periods of somatic and dendritic spikes. A high threshold class of K+ channel, AptKv3.3, is expressed at high levels and distributed over the entire soma-dendritic axis of pyramidal cells. AptKv3.3 channels are shown to contribute to the repolarization of both somatic and dendritic spikes, with pharmacological blockade of dendritic Kv3 channels revealing an important role in controlling the threshold for burst discharge. The entire process of conditional back-propagation and burst output is successfully simulated using a new compartmental model of pyramidal cells that incorporates a cumulative inactivation of dendritic K+ channels during repetitive discharge. This work is important in demonstrating how the success of spike backpropagation can control the output of a principle sensory neuron, and how this process is regulated by the distribution and properties of voltage-dependent K+ channels.     

Neuronal Spike Initiation Modulated by Extracellular Electric Fields

Based on a reduced two-compartment model, the dynamical and biophysical mechanism underlying the spike initiation of the neuron to extracellular electric fields is investigated in this paper. With stability and phase plane analysis, we first investigate in detail the dynamical properties of neuronal spike initiation induced by geometric parameter and internal coupling conductance. The geometric parameter is the ratio between soma area and total membrane area, which describes the proportion of area occupied by somatic chamber. It is found that varying it could qualitatively alter the bifurcation structures of equilibrium as well as neuronal phase portraits, which remain unchanged when varying internal coupling conductance. By analyzing the activating properties of somatic membrane currents at subthreshold potentials, we explore the relevant biophysical basis of spike initiation dynamics induced by these two parameters. It is observed that increasing geometric parameter could greatly decrease the intensity of the internal current flowing from soma to dendrite, which switches spike initiation dynamics from Hopf bifurcation to SNIC bifurcation; increasing internal coupling conductance could lead to the increase of this outward internal current, whereas the increasing range is so small that it could not qualitatively alter the spike initiation dynamics. These results highlight that neuronal geometric parameter is a crucial factor in determining the spike initiation dynamics to electric fields. The finding is useful to interpret the functional significance of neuronal biophysical properties in their encoding dynamics, which could contribute to uncovering how neuron encodes electric field signals.