A dendritic cable model for the amplification of synaptic potentials by an ensemble average of persistent sodium channels

The persistent sodium current density (I(NaP)) at the soma measured with the 'whole-cell' patch-clamp recording method is linearized about the resting state and used as a current source along the dendritic cable (depicting the spatial distribution of voltage-dependent persistent sodium ionic channels). This procedure allows time-dependent analytical solutions to be obtained for the membrane depolarization. Computer simulated response to a dendritic current injection in the form of synaptically-induced voltage change located at a distance from the recording site in a cable with unequally distributed persistent sodium ion channel densities per unit length of cable (the so-called 'hot-spots') is used to obtain conclusions on the density and distribution of persistent sodium ion channels. It is shown that the excitatory postsynaptic potentials (EPSPs) are amplified if hot-spots of persistent sodium ion channels are spatially distributed along the dendritic cable, with the local density of I(NaP) with respect to the recording site shown to specifically increase the peak amplitude of the EPSP for a proximally placed synaptic input, while the spatial distribution of I(NaP) serves to broaden the time course of the amplified EPSP. However, in the case of a distally positioned synaptic input, both local and nonlocal densities yield an approximately identical enhancement of EPSPs in contradiction to the computer simulations performed by Lipowsky et al. [J. Neurophysiol. 76 (1996) 2181]. The results indicate that persistent sodium channels produce EPSP amplification even when their distribution is relatively sparse (i.e. , approximately 1-2% of the transient sodium channels are found in dendrites of CA1 hippocampal pyramidal neurons). This gives a strong impetus for the use of the theory as a novel approach in the investigation of synaptic integration of signals in active dendrites represented as ionic cables.     

Long-term potentiation in the neurons of the edible snail

A brief high-frequency stimulation of the anal nerve of the isolated nerve ring of snail Helix induced a pronounced increase in the amplitude of EPSPs, evoked in identified neurons of left parietal and visceral ganglions by low frequency (once in 5 min) stimulation of the same nerve. The amplitude of EPSP returned to the control level 30-120 min after tetanization. We called this effect long-term potentiation. A brief application of serotonin (10 microM) in the majority of neurons also induced lasting either 15-30 min or more than 2 hours facilitation of EPSP, evoked by anal nerve stimulation. Intracellular cAMP injections, being without effect on EPSP amplitude in many neurons, in certain neurons caused an increase in EPSP amplitude, lasting up to 30 min. It is suggested that the 3 factors shown to increase synaptic efficiency in molluscan neurons may have common mechanisms of action.     

Electrical advantages of dendritic spines

Many neurons receive excitatory glutamatergic input almost exclusively onto dendritic spines. In the absence of spines, the amplitudes and kinetics of excitatory postsynaptic potentials (EPSPs) at the site of synaptic input are highly variable and depend on dendritic location. We hypothesized that dendritic spines standardize the local geometry at the site of synaptic input, thereby reducing location-dependent variability of local EPSP properties. We tested this hypothesis using computational models of simplified and morphologically realistic spiny neurons that allow direct comparison of EPSPs generated on spine heads with EPSPs generated on dendritic shafts at the same dendritic locations. In all morphologies tested, spines greatly reduced location-dependent variability of local EPSP amplitude and kinetics, while having minimal impact on EPSPs measured at the soma. Spine-dependent standardization of local EPSP properties persisted across a range of physiologically relevant spine neck resistances, and in models with variable neck resistances. By reducing the variability of local EPSPs, spines standardized synaptic activation of NMDA receptors and voltage-gated calcium channels. Furthermore, spines enhanced activation of NMDA receptors and facilitated the generation of NMDA spikes and axonal action potentials in response to synaptic input. Finally, we show that dynamic regulation of spine neck geometry can preserve local EPSP properties following plasticity-driven changes in synaptic strength, but is inefficient in modifying the amplitude of EPSPs in other cellular compartments. These observations suggest that one function of dendritic spines is to standardize local EPSP properties throughout the dendritic tree, thereby allowing neurons to use similar voltage-sensitive postsynaptic mechanisms at all dendritic locations.     

Computer simulation study of the relationship between the profile of excitatory postsynaptic potential and stimulus-correlated motoneuron firing

This paper shows the results of computer simulation of changes in motoneuron (MN) firing evoked by a repetitively applied synaptic volley that consists of a single excitatory postsynaptic potential (EPSP). Spike trains produced by the threshold-crossing MN model were analyzed as experimental results. Various output functions were applied for analysis; the most useful was a peristimulus time histogram, a special modification of a raster plot and a peristimulus time frequencygram (PSTF). It has been shown that all functions complement each other in distinguishing between the genuine results evoked by the excitatory volley and the secondary results of the EPSP-evoked synchronization. The EPSP rising edge was best reproduced by the PSTF. However, whereas the EPSP rise time could be estimated quite accurately, especially for high EPSP amplitudes at high MN firing rates, the EPSP amplitude estimate was also influenced by factors unrelated to the synaptic volley, such as the afterhyperpolarization duration of the MN or the amplitude of synaptic noise, which cannot be directly assessed in human experiments. Thus, the attempts to scale any estimate of the EPSP amplitude in millivolts appear to be useless. The decaying phase of the EPSP cannot be reproduced accurately by any of the functions. For the short EPSPs, it is extinguished by the generation of an action potential and a subsequent decrease in the MN excitability. For longer EPSPs, it is inseparable from the secondary effects of synchronization. Thus, the methods aimed at extracting information about long-lasting and complex postsynaptic potentials from stimulus-correlated MN firing, should be refined, and the theoretical considerations checked in computer simulations.     

Spine calcium transients induced by synaptically-evoked action potentials can predict synapse location and establish synaptic democracy

CA1 pyramidal neurons receive hundreds of synaptic inputs at different distances from the soma. Distance-dependent synaptic scaling enables distal and proximal synapses to influence the somatic membrane equally, a phenomenon called "synaptic democracy". How this is established is unclear. The backpropagating action potential (BAP) is hypothesised to provide distance-dependent information to synapses, allowing synaptic strengths to scale accordingly. Experimental measurements show that a BAP evoked by current injection at the soma causes calcium currents in the apical shaft whose amplitudes decay with distance from the soma. However, in vivo action potentials are not induced by somatic current injection but by synaptic inputs along the dendrites, which creates a different excitable state of the dendrites. Due to technical limitations, it is not possible to study experimentally whether distance information can also be provided by synaptically-evoked BAPs. Therefore we adapted a realistic morphological and electrophysiological model to measure BAP-induced voltage and calcium signals in spines after Schaffer collateral synapse stimulation. We show that peak calcium concentration is highly correlated with soma-synapse distance under a number of physiologically-realistic suprathreshold stimulation regimes and for a range of dendritic morphologies. Peak calcium levels also predicted the attenuation of the EPSP across the dendritic tree. Furthermore, we show that peak calcium can be used to set up a synaptic democracy in a homeostatic manner, whereby synapses regulate their synaptic strength on the basis of the difference between peak calcium and a uniform target value. We conclude that information derived from synaptically-generated BAPs can indicate synapse location and can subsequently be utilised to implement a synaptic democracy.     

刺激鲫鱼小脑腹外侧区诱发的Mauthner细胞兴奋性突触后电位

实验采用微电极胞内记录技术探查鲫鱼Mauthner细胞(M-细胞)对小脑刺激的电反应特征。电刺激鲫鱼小脑腹外侧部,可在双侧M-细胞胞体、腹侧树突和外侧树突近端记录到一种复合性兴奋性突触后电位(小脑诱发性EPSP)。小脑诱发性EPSP潜伏期较短(0.63±0.09 ms),持续时间较长(5.49±1.13 ms),幅度分级和刺激频率依从等特征。以较高强度刺激小脑常引起M-细胞顺向激活。多点胞内连续穿刺实验显示小脑诱发性EPSP起源于腹侧树突远端。实验结果提示,小脑-M-细胞通路可能包含一组长短不等的神经元链,它们根据链的短或长,由近及远依次投射在腹侧树突远端。     

Transient Response in a Dendritic Neuron Model for Current Injected at One Branch

Mathematical expressions are obtained for the response function corresponding to an instantaneous pulse of current injected to a single dendritic branch in a branched dendritic neuron model. The theoretical model assumes passive membrane properties and the equivalent cylinder constraint on branch diameters. The response function when used in a convolution formula enables one to compute the voltage transient at any specified point in the dendritic tree for an arbitrary current injection at a given input location. A particular numerical example, for a brief current injection at a branch terminal, illustrates the attenuation and delay characteristics of the depolarization peak as it spreads throughout the neuron model. In contrast to the severe attenuation of voltage transients from branch input sites to the soma, the fraction of total input charge actually delivered to the soma and other trees is calculated to be about one-half. This fraction is independent of the input time course. Other numerical examples, which compare a branch terminal input site with a soma input site, demonstrate that, for a given transient current injection, the peak depolarization is not proportional to the input resistance at the injection site and, for a given synaptic conductance transient, the effective synaptic driving potential can be significantly reduced, resulting in less synaptic current flow and charge, for a branch input site. Also, for the synaptic case, the two inputs are compared on the basis of the excitatory post-synaptic potential (EPSP) seen at the soma and the total charge delivered to the soma.     

Quantitative analysis of electrical properties of dendritic spines

Several sugestions have been made with regard to the functional significance of dendritic spines in connection with synaptic plasticity. We have shown that for a constant synaptic current, when the synaptic resistance is large compared to the spine-stem resistance, a morphological change in the spine does not produce a marked change in the postsynaptic potential (PSP). When the synaptic resistance is comparable to the spine-stem impedance a morphological change in the spine can induce changes in the synaptic current and the PSP due to the so-called nonlinear effect to the synapse (Kawato and Tsukahara, 1983, 1984). Consequently, in a study of the electrical properties of dendritic spines the input impedance of the parent dendrite, the spinestalk conductance and the conductance change associated with synaptic activity must be considered. We quantitatively estimated all three factors. By comparing electrophysiological data with morphological data, we estimated the synaptic conductance which causes corticorubral EPSP. Its maximum amplitude was 43 nS with a time-to-peak value of 0.3 ms. With this value, the effects of the spine were examined using an improved algorithm based on that of Butz and Cowan (1974). It uses a three-dimensional morphology of the rubrospinal (RS) neurons, which was reconstructed from serial sections containing HRP-filled RS cells. As the spine shortens, the amplitude of the EPSP becomes considerably larger, but its time-to-peak value does not markedly change. Moreover, if unitary EPSP in the RS cell is produced by the activation of several synaptic terminals a morphological change of the spine has a smaller effect on the EPSPs.     

Characteristics of electrical activity of olfactory bulb neurons of fish

It was shown by intracellular recording of the activity of olfactory bulb neurons of the carp that their dendrites are excited both by synaptic activation and by direct stimulation with an electric current. The dendrites generate an action potential and probably conduct it for some distance toward the soma. The neurons can be divided into two groups: one responds to ortho- and antidromic stimuli with one, rarely with two peaks, the other responds with a rhythmical discharge. The presence of early and late IPSP is characteristic of neurons of both groups. Rhythmical variations in potential with a frequency of 26–33/sec, so-called oscillations, are recorded; they may be excitatory (in secondary neurons they correspond to EPSP) or inhibitory (they correspond to IPSP). Possible mechanisms of the excitatory oscillations and the rhythmical discharge in olfactory bulb neurons of the carp are discussed.M. V. Lomonosov Moscow State University. Translated from Neirofiziologiya, Vol.3, No.5, pp. 505–511, September–October, 1971.     

Influence of the Geometry of an Axo-Dendritic Synapse and Its Position on the Dendrite on the Current Recorded from the Neuronal Soma

Using mathematical simulation,we studied the influence of the geometry of an axo-dendritic synapse and its position on the dendrite on the value of the postsynaptic current that arrives at the soma. It was shown that the geometric dimensions of the synaptic cleft and the conductance of postsynaptic receptor-channel complexes determine the value of the current coming into the postsynaptic cell, while the geometry and conductance of the dendrite determine the part of this current arriving at the soma. At a constant conductance of the postsynaptic membrane but with an increase in the diameter of the synaptic contact and a decrease in the width of the synaptic cleft, the current coming into the postsynaptic unit decreases, but the reversal potential for this current under these conditions does not change. Vice versa, influences determined by changes in the geometry and ion conductance of the dendrite membrane are capable not only of decreasing the current injected into the soma but also of changing its reversal potential. The thinner the dendrite and the more distant the location of the synapse from the soma, the more significant such effects. Neirofiziologiya/Neurophysiology, Vol. 37, No. 2, pp. 101–107, March–April, 2005.     

Microinjection of mRNA encoding rat synapsin Ia alters synaptic physiology in identified motoneurons of the crayfish,Procambarus clarkii

Studies of identified neurons have made important contributions to our understanding of cellular neurophysiology. We have developed a technique for modifying gene expression in identified motoneurons of the crayfish Procambarus clarkii in the isolated nervous system as well as in the intact animal through the injection of exogenously synthesized RNAs. mRNA suitable for injection was transcribed in vitro from cDNA templates cloned into a plasmid, pSEM. Initially, mRNAs encoding green fluorescent protein (GFP) and β-galactosidase were injected into the soma of the motor giant neuron (MoG) to determine whether these mRNAs could be successfully translated into protein. Both proteins were expressed. Measurements of GFP fluorescence increase indicated that GFP mRNA was stable and translated into protein for at least 3 days postinjection. We then examined the effects of expression of GFP, AASP-168 (an endogenous crayfish axonal protein), and rat synapsin Ia on MoG synaptic physiology. The mRNA injection procedure did not appear to directly influence synaptic physiology based on the results of the AASP-168 and GFP injections. Injection of mRNA encoding rat synapsin Ia resulted in a significant increase in peak excitatory postsynaptic potential (EPSP) amplitude during repetitive stimulation. These data are consistent with previous studies that have shown that synapsin deficiency reduces synaptic vesicle numbers. The translation of mRNAs with diverse functions and species of origin suggests that this approach will prove useful for studying the function of a wide variety of endogenous and exogenous genes in identified neurons. © 1998 John Wiley & Sons, Inc. J Neurobiol 37: 224–236, 1998     

A persistent postsynaptic modification mediates long-term potentiation in the hippocampus

Long-term potentiation (LTP) is a long-lasting enhancement of synaptic transmission that can be induced by brief repetitive stimulation of excitatory pathways in the hippocampus. One of the most controversial points is whether the process underlying the enhanced synaptic transmission occurs pre- or postsynaptically. To examine this question, we have taken advantage of the novel physiological properties of excitatory synaptic transmission in the CA1 region of the hippocampus. Synaptically released glutamate activates both NMDA and non-NMDA receptors on pyramidal cells, resulting in an excitatory postsynaptic potential (EPSP) with two distinct components. A selective increase in the non-NMDA component of the EPSP was observed with LTP. This result suggests that the enhancement of synaptic transmission during LTP is caused by an increased sensitivity of the postsynaptic neuron to synaptically released glutamate.     

Multicomponent synaptic potentials in rubrospinal neurons of cat brain evoked by corticofugal impulses

The compound nature of EPSP occurring in response to stimulation of the sensorimotor area of the cerebral cortex and the association area of the parietal cortex was shown during acute experiments on cats anesthetized by pentobarbital using an intracellular recording technique. The monosynaptic nature of the two first components of EPSP produced by corticofugal impulses spreading at the average rate of 18.5 and 7.5 msec, respectively, was established. It is postulated that these EPSP components are produced by activating the slow conducting pyramidal and corticorubral neurons. In a portion of rubrospinal neurons the first component of EPSP produced by corticofugal impulses was marked by a fast-rising phase and reflected electrophysiological activation of axosomatic synapses. Findings are discussed with regard to mechanisms reorganizing cortical synaptic inputs to the red nucleus neurons.L. A. Orbeli Institute of Physiology, Academy of Sciences of the Armenian SSR, Erevan. Translated from Neirofiziologiya, Vol. 17, No. 5, pp. 665–672, September–October, 1985.     

Multiplicity of pacemaker zones in Helix pomatia neurons

Intracellular microelectrode recordings from neurons ofHelix pomatia revealed several local zones of action potential generation both on the soma and on some of the branches of the neurons. Under certain conditions the activity of individual loci of the neuron membrane was synchronized to produce a normal action potential. It is suggested that the somatic membrane of neurons is heterogeneous in structure and consists of separate loci of an electrically excitable membrane, incorporating active and latent pacemaker zones. Neurons ofH. pomatia are characterized by two types of action potential with different triggering mechanisms: one (synaptic) type is generated under the influence of the EPSP, the other (pacemaker) arises through activation of endogenous factors for the neuron (pacemaker potentials). The interaction between synaptic and pacemaker potentials during integrative activity of the neuron is discussed.M. V. Lomonosov Moscow State University. Translated from Neirofiziologiya, Vol. 5, No. 1, pp. 88–94, January–February, 1973.     

Effect of serotonin and noradrenaline on the magnitude of the response of the command neurons for defensive behavior in Helix lucorum L

Changes in synaptic responses of identified command neurones of avoidance behaviour to the electric nerve stimulation were investigated in the isolated nervous system of the snail during bath application of serotonin or noradrenaline. Serotonin (10(-5) M) elicited an increase of summary EPSP amplitude in the cells without changes of input resistance and resting potential. Noradrenaline (10(-5) M) application evoked an increase of EPSP amplitude, accompanied by an increase of the input resistance. Mechanisms of serotonin and noradrenaline influence on synaptic responses are discussed.     

A Study of the Role of GABAA- and GABAB-Receptors in Presynaptic Inhibition of Primary Afferents in the Spinal Cord of the Frog Rana ridibunda

The role of GABA_A- and GABA_B-receptors in presynaptic inhibition of primary afferent fibers was studied on an isolated preparation of the spinal cord of the frog Rana ridibunda. It is shown that the inhibitory effect of GABA on synaptic transmission from afferent fiber to motoneuron is caused by activation of both GABA_A- and GABA_B-receptors. A temporal correlation (± 5 min) was shown between the blocking action of bicuculline (a specific antagonist of GABA_A-receptors) on primary afferent fiber depolarization (PAD) and its potentiating effect on the excitatory postsynaptic potential (EPSP) at parallel intracellular recording of EPSP in motoneuron and PAD in axons of the dorsal root. As a basis of this correlation, the single GABA_A-receptor mechanism is discussed, which mediates the effect of bicuculline on PAD and EPSP. When a specific agonist of GABA_B-receptor, baclofen, and an antagonist of GABA_B-receptor, 2(OH)-saclofen, were applied, the obtained data indicated an involvement of GABA_B-receptors in inhibition of synaptic transmission from afferent fibers to the motoneuron. Analysis of parameters of the unitary synaptic responses recorded in the control experiments and of their changes under the effect of (– )-baclofen indicates that the inhibitory action caused by activation of GABA_B-receptors develops at the presynaptic level.     

Study of role of inhibitory interneurons in mechanisms of regulation of sensory synapses formed by thalamic and cortical inputs on pyramidal cells of the dorsolateral amygdala nucleus

The work deals with study of role of inhibitory interneurons in the process of regulation of sensory currents converging on soma of pyramidal cells of the dorsolateral amygdala nucleus as well as of role of these interneurons in mechanism of regulation of plasticity of amygdala synapses. It has been shown that the part of the spontaneous inhibitory postsynaptic currents recorded on the dorsolateral amygdala pyramidal cells is relatively high and amounts to about a half of the total amount of the recorded events. Analysis of the evoked postsynaptic responses has shown the interneurons to regulate activity and duration of these responses due to the postsynaptic membrane hyperpolarization as a result of activation of GABA_A-receptors. Also studied was role of interneurons in providing mechanisms of the long-term potentiation of the synaptic responses evoked by stimulation of cortical and thalamic inputs. Block of effect of interneurons with help of picrotoxin has been shown to lead to an increase of evoked potentiation of synaptic responses.     

Contribution of a humoral factor to postsynaptic sensitization in heterosynaptic facilitation

It was shown that heterosynaptic facilitation develops in the cerebral ganglia giant neurons of the freshwater gastropod molluskPlanorbis corn eus due to diffuse neurohumoral influences on pre- and postsynaptic structures and not local synaptic action on presynaptic mechanisms. It was also found that n-cholinergic synaptic mechanisms come under this facilitatory influence. Serotonin is the source of facilitation in neurons of bothPlanorbis corneus cerebral ganglion and those of the aplysia abdominal ganglion. Seeing that: a) conditioning stimuli facilitate the effects produced by iontophoretic acetylcholine application, as well as n-cholinergic synaptic transmission and b) the amplitude of EPSP and acetylcholine potential increase 4–6 times during facilitation when the input impedance of the post-synaptic membrane is increased by just 20%, it was deduced that the postsynaptic membrane of the giant neuron makes a significant contribution to heterosynaptic facilitation of the sensitization of n-cholinergic receptors. The part played by n-cholinergic receptors of the postsynaptic membrane in heterosynaptic facilitation and conditioned reflex habituation is discussed.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 18, No. 2, pp. 250–259, March–April, 1986.     

The heterogeneity of the excitatory synaptic inputs in the spinal motor neurons of the frog Rana ridibunda

The synaptic responses induced in motoneurones by the stimulations of the dorsal root (DR), single afferent fibres and reticular formation (RF) were intracellularly recorded in the isolated frog spinal cord. It was shown that argiopine (the selective blocker of glutamate receptors of non-NMDA type) in concentrations ranging from 3.10(-7) to 1.10(-5) M effectively suppressed the di- and polysynaptic, but not the monosynaptic components of EPSP's induced by DR stimulation. The initial reaction to argiopine consisted of the increase of this monosynaptic component of EPSP. In the same concentrations range, argiopine reduced both mono- and polysynaptic EPSP, evoked by RF stimulation. 2-amino-phosphonovaleric acid (1.10(-4) M) did not affect, whereas the kinurenate (1--2.10(-3) M) completely blocked the amplitude of all kinds of synaptic responses. The various effects of argiopine on the responses induced by microstimulation of presynaptic nerve terminals were observed. The data obtained speak in favour of heterogeneity of monosynaptic excitatory inputs in the motoneurones of frog spinal cord. Being the glutamatergic by nature, the inputs differ in the properties of postsynaptic receptors. All of these receptors concerning to non NMDA-type can be divided to argiopine-sensitive and argiopine-resistant. The first seem to be involved in the monosynaptic connections of RF and the second--in those of primary afferents with motoneurones.     

Synaptic nature of the principal components of the evoked potential in the general cortex of the turtle forebrain

The nature of the principal components of the evoked potential of the general cortex of the turtle forebrain was studied in response to electrical stimulation of the contralateral optic nerve. Comparison of these components with postsynaptic potentials of the neurons of this structure showed that the four fast negative waves of the evoked potential correspond to fast EPSPs, which are independent of one another. The positive wave of the evoked potential is the sum of several IPSPs. The slow negative and, to some extent, the positive wave are a reflection of the slow EPSP. It is shown that early EPSPs are generated on portions of the apical dendrites which are further from the soma than those generating late fast EPSPs and also the IPSP and slow EPSP. Axo-somatic contacts are perhaps also concerned in the generation of the last-named potential.M. V. Lomonosov Moscow State University. Translated from Neirofiziologiya, Vol. 5, No.3, pp.261–271, May–June, 1973.