Computer simulation of neurone pattern processing

Physiological simulation techniques can provide a very useful additional tool with which to explore the behaviour of neurones, especially for probing those areas that are not easily accessible to experimental monitoring techniques such as activity in the dendrites. This paper explores the information processing capabilities of a cerebral cortical pyramidal neurone using a computer simulation. The computer model simulated two important aspects of pyramidal cell behaviour: the transient distribution of membrane potential over a proportion of the apical dendritic tree of the cell, and the ability of the receptors in the neurones' dendritic spines to undergo plastic changes. The simulation of receptor behaviour modelled the ability of receptor regions to increase their sensitivity if a prior input had occurred when the spine head membrane was depolarized. The model was used to explore the response of the cell to different inputs. It underlined the need for large amounts of local activity before spinal receptors changed their sensitivity. It also demonstrated the ability of pyramidal cells to both recognize patterns of input and to associate one pattern of inputs with another. It is argued that this pattern association property could be a neuronal basis for association learning.     

Functionally opposite receptors on neurones.

According to the second general principle of chemical neurotransmission, formulated by Eccles, a neurotransmitter released from the axonal terminals of a neurone has only one and the same effect on all the follower cells: all the follower cells are either excited or inhibited by it. The evidence reviewed in this paper suggests that there may be some exceptions to this general pattern of synaptic organisation. The co-existence of both excitatory and inhibitory receptors for the same transmitter substance on the same neuronal membrane has been described in invertebrates: ‘opposite receptors’ can occur for acetylcholine, dopamine and glutamate. There is also evidence suggesting the existence of opposite receptors for acetylcholine and nonadrenaline on neurones in the mammalian brain. The activation of functionally opposite receptors results in ‘antagonistic agonism’: the net pharmacological effect is obtained by the algebraic summation of the two opposing component effects. Both the time-course and the polarity of neuronal responses to a given neurotransmitter is influenced by the relationship between the two kinds of receptor. It is suggested that both pre-synaptic and post-synaptic factors may modify this relationship.     

Basic module for an adaptive control system based on neurone information processing

The design of such devices as robotic aids for handicapped people, powered prostheses and manipulative aids such as page turners would benefit from the use of an adaptive control system. Much recent work on adaptive networks has been based on simplified models of the information processing capabilities of neurones. Neurones are now known to be capable of association learning and memory and this study incorporates these features in a neurone model. A single neuronal input system, the NMDA-type glutamate receptor, is modelled by deriving finite difference equations from its reaction dynamics so that the concentration of several molecules in the receptor can be plotted as a function of time. The model shows association learning taking place at the glutamate receptor. A whole neurone with ten glutamate receptor regions is also modelled and shows that a neurone should be capable of recognizing patterns of inputs. As the neurone model is complicated and slow to run, a much simplified form of the model is described which embodies the basic features of neurone information processing in a simple algorithm.     

NO donors transform neuronal response to glutamate

Electrophysiological experiments on three identified neurones were performed. Two NO donors, sodium nitroprusside (SNP) and sodium nitrite, as well as NO synthase inhibitor, were used. In each neurone, bath application of glutamate caused hyperpolarization and suppression of firing. Combined application of glutamate and SNP resulted in that the same cells responded to identical glutamate solutions with depolarization and excitation. Application of N-monomethyl-L-arginin (NMMA) arrested the glutamate-induced firing and depolarization. The findings suggest involvement of NO in the mechanism of transformation of glutamate-induced inhibition into excitation and a mediation of the latter by the N-methyl-D-aspartate-like receptors in the Helix brain.     

A hybrid computer model of stochastic activity of the neurone

The authors describe a hybrid computer neurone model intended for the investigation of stochastic transformations effected by neurones in correlation to some of their physiological parameters. The model is designed so as to give the best possible characterization of the internal dynamics of a neurone with minimum limiting conditions. It allows the generation of suitable input stochastic processes or operates with input processes obtained experimentally in the living neurone and it carries out basic statistical tests of the output stochastic process.     

Effect of serotonin on the activity of the neurons involved in the realization of the avoidance reflex of the snail

Bath application of 10(-5) mol/l of serotonin (5-HT) elicited a 50% increase of summary EPSPs recorded in command neurones for avoidance behaviour. No significant changes of rest potential and input resistance were seen in these cells. 5-HT evoked an increase of spontaneous level of firing in motoneurones involved in the same reflex, as well as an increase in the number of spikes which paralleled increase of EPSPs to the same stimulus in command neurones. In sensory cells, presynaptic to the command neurones, application of 5-HT evoked a significant increase of excitability and of input resistance. Monosynaptic EPSPs recorded in the command neurones showed a 40% increase after serotonin application. It is concluded that the major locus of plastic changes evoked by 5-HT application in the neuronal chain underlying avoidance reflex is the synaptic contact between sensory and command neurones.     

Edited GluR2, a gatekeeper for motor neurone survival?

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disorder of motor neurones. Although the genetic basis of familial forms of ALS has been well explored, the molecular basis of sporadic ALS is less well understood. Recent evidence has linked sporadic ALS with the failure to edit key residues in ionotropic glutamate receptors, resulting in excessive influx of calcium ions into motor neurones which in turn triggers cell death. Here we suggest that edited AMPA glutamate (GluR2) receptor subunits serve as gatekeepers for motor neurone survival.     

Early events in glutamate receptor trafficking

Glutamate receptors are the primary mediators of excitatory synaptic transmission in the mammalian central nervous system. Activity-dependent changes in the number of postsynaptic glutamate receptors underlie aspects of synaptic plasticity and provide a mechanism for information storage in the brain. Recent work shows that receptor exit from the endoplasmic reticulum represents a critical regulatory step in glutamate receptor trafficking to the neuronal cell surface.     

Excitotoxic loss of post-synaptic sites is distinct temporally and mechanistically from neuronal death

Dendritic degeneration and loss of synaptic proteins are early events correlated with functional decline in neurodegenerative disease. The temporal and mechanistic relationship between synapse loss and cell death, however, remains unclear. We used confocal microscopy and image processing to count post-synaptic sites on rat hippocampal neurons by expressing post-synaptic density protein 95 fused to green fluorescent protein. Fluorescent puncta co-localized with neurotransmitter release sites, NMDA-induced Ca²⁺ increases and NMDA receptor immunoreactivity. During excitotoxic neurodegeneration, synaptic sites were lost and synaptic transmission impaired. These changes were mediated by NMDA receptors and required Ca²⁺-dependent activation of the proteasome pathway. Tracking synapses from the same cell following brief neurotoxic insult revealed transient loss followed by recovery. The time-course, concentration-dependence and mechanism for loss of post-synaptic sites were distinct from those leading to cell death. Cells expressing p14ARF, which inhibits ubiquitination of post-synaptic density protein 95 and prevents loss of synaptic sites, displayed an increased sensitivity to glutamate-induced cell death. Thus, excitotoxic synapse loss may be a disease-modifying process rather than an obligatory step leading to cell death. These results demonstrate the importance of assessing synaptic function independent of neuronal survival during neurodegeneration and indicate that this approach will be useful for identifying toxins that degrade synaptic connections and for screening for agents that protect synaptic function.     

A Brownian model of glutamate diffusion in excitatory synapses of hippocampus

We simulated the diffusion of glutamate, following the release of a single vesicle from a pre-synaptic terminal, in the synaptic cleft by using a Brownian diffusion model based on Langevin equations. The synaptic concentration time course and the time course of quantal excitatory post-synaptic current have been analyzed. The results showed that they depend on the number of receptors located at post-synaptic membrane. Their time course are dependent both on the total number of the post-synaptic receptors and on the eccentricity of the pre-synaptic glutamate vesicle.     

Coding with spike shapes and graded potentials in cortical networks

In cortical neurones, analogue dendritic potentials are thought to be encoded into patterns of digital spikes. According to this view, neuronal codes and computations are based on the temporal patterns of spikes: spike times, bursts or spike rates. Recently, we proposed an 'action potential waveform code' for cortical pyramidal neurones in which the spike shape carries information. Broader somatic action potentials are reliably produced in response to higher conductance input, allowing for four times more information transfer than spike times alone. This information is preserved during synaptic integration in a single neurone, as back-propagating action potentials of diverse shapes differentially shunt incoming postsynaptic potentials and so participate in the next round of spike generation. An open question has been whether the information in action potential waveforms can also survive axonal conduction and directly influence synaptic transmission to neighbouring neurones. Several new findings have now brought new light to this subject, showing cortical information processing that transcends the classical models.     

Neurophysiology of the vibration sense in locusts and bushcrickets: The responses of ventral-cord neurones

In the locustid Locusta migratoria and the tettigoniids Decticus verrucivorus and Tettigonia cantans, comparative aspects of physiological properties of vibratory/auditory ventral-cord neurones were studied by single cell recordings.These neurones all receive inputs from both vibratory and auditory receptors. Nevertheless, they can be classified into “V neurones” responding preferentially to vibration stimuli, “VS neurones” responding to vibration and airborne sound, and “S neurones” responding preferentially to airborne sound. In every group, there are several types with different physiological properties, normally represented by one neurone on each body side.In Locusta and in the tettigoniid species, the same physiological types of vibratory/auditory neurones were found, although there are differences in the synaptic connectivity of the vibration receptors of the different legs. In Locusta, the middle leg receptors have the strongest influence on the generation of suprathreshold responses of the central neurones, whereas in the tettigoniids the receptors of the ipsilateral fore leg are the most influential.Two of the V neurones receive inputs mainly from campaniform sensilla and other low-frequency vibration receptors, the other V and VS neurones are mainly influenced by the subgenual receptors. Central information processing results in preferential responses to different frequency/intensity ranges in different neurones.Most VS neurone types show the same response characteristics (e.g. time pattern of response, habituation) either to vibration or to airborne-sound stimuli. Simultaneous presentation of both stimuli leads to qualitative changes in the response characteristics. Therefore, the co-processing of auditory and vibratory signals seems to be very important in the acoustic behaviour of grasshoppers.     

Development and characterisation of a glutamate-sensitive motor neurone cell line

Modification of the growth conditions of NSC-34 mouse neuroblastoma x motor neurone cells by serum depletion promotes the expression of functional glutamate receptors as the cells mature into a form that bears the phenotypic characterisation of motor neurones. Immunocytochemical studies demonstrated the presence of the glutamate receptor proteins NMDAR1, NMDAR2A/B, GluR1, GluR2, GluR2/3, GluR4, GluR6/7, and KA2. Toxicity assays using cell counting techniques demonstrated a mild but significant cell death (approximately 30%, p < 0.01) following a 24-h exposure to 1 mM glutamate that could be prevented by the presence of the glutamate receptor antagonists (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (10 microM) and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulphonamide (1 microM). As an indication of glutamate receptor functional activity a novel approach was used to detect the production of free radicals following stimulation with glutamate receptor agonists. The release of superoxide free radicals was detected using a micro-electrochemical sensor following addition of glutamate receptor agonists to the cell bathing solution. Alterations in intracellular calcium concentrations were examined using fura-2 imaging. Exposure of the differentiated NSC-34 cells to glutamate leads to an increase in intracellular calcium concentrations that is prevented by the presence of glutamate receptor antagonists. The motor neurone origin of these cells makes them particularly useful for investigating the potential role of glutamatergic toxicity in motor neurone degeneration.     

Calcium influx through subunits GluR1/GluR3 of kainate/AMPA receptor channels is regulated by cAMP dependent protein kinase.

Excitatory synaptic transmission in the central nervous system (CNS) is mediated by three major classes of glutamate receptors, namely the ionotropic NMDA (N-Methyl-D-Aspartate) and KA/AMPA (kainate/alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid) receptors and the metabotropic receptor type. Among the ionotropic receptors, NMDA receptors are thought to mediate their physiological response mainly through the influx of extracellular calcium, while KA/AMPA receptor channels are mainly thought to carry the influx of monovalent cations. Recently, we have challenged this view by showing that cloned KA/AMPA receptor subunits GluR1 and GluR3 form ion channels which are permeable to calcium. We now directly demonstrate large increases in intracellular calcium concentrations induced by calcium fluxes through KA/AMPA receptor channels in solutions with physiological calcium concentrations. Calcium fluxes were observed through glutamate receptor channels composed of the subunits GluR1 and GluR3, which are both abundantly present in various types of central neurones. The calcium influx was fluorometrically monitored in Xenopus oocytes injected with the calcium indicator dye fura-2. Bath application of the membrane permeable analogue of adenosine cyclic monophosphate (cAMP) potentiated the current and also the flux of calcium through open KA/AMPA receptor channels. Further pharmacological experiments suggested that this effect was mediated by the activation of protein kinase A. Our results provide a molecular interpretation for the function of calcium permeable KA/AMPA receptor channels in neurones and identify two of the subunits of the KA/AMPA receptor channel which are regulated by the cAMP dependent second messenger system.     

Emergence of network structure due to spike-timing-dependent plasticity in recurrent neuronal networks. I. Input selectivity–strengthening correlated input pathways

Spike-timing-dependent plasticity (STDP) determines the evolution of the synaptic weights according to their pre- and post-synaptic activity, which in turn changes the neuronal activity. In this paper, we extend previous studies of input selectivity induced by (STDP) for single neurons to the biologically interesting case of a neuronal network with fixed recurrent connections and plastic connections from external pools of input neurons. We use a theoretical framework based on the Poisson neuron model to analytically describe the network dynamics (firing rates and spike-time correlations) and thus the evolution of the synaptic weights. This framework incorporates the time course of the post-synaptic potentials and synaptic delays. Our analysis focuses on the asymptotic states of a network stimulated by two homogeneous pools of “steady” inputs, namely Poisson spike trains which have fixed firing rates and spike-time correlations. The (STDP) model extends rate-based learning in that it can implement, at the same time, both a stabilization of the individual neuron firing rates and a slower weight specialization depending on the input spike-time correlations. When one input pathway has stronger within-pool correlations, the resulting synaptic dynamics induced by (STDP) are shown to be similar to those arising in the case of a purely feed-forward network: the weights from the more correlated inputs are potentiated at the expense of the remaining input connections.     

Excitatory synaptic currents in Purkinje cells

The N-methyl-D-aspartate (NMDA) and non-NMDA classes of glutamate receptor combine in many regions of the central nervous system to form a dual-component excitatory postsynaptic current. Non-NMDA receptors mediate synaptic transmission at the resting potential, whereas NMDA receptors contribute during periods of postsynaptic depolarization and play a role in the generation of long-term synaptic potentiation. To investigate the receptor types underlying excitatory synaptic transmission in the cerebellum, we have recorded excitatory postsynaptic currents (EPSCS), by using whole-cell techniques, from Purkinje cells in adult rat cerebellar slices. Stimulation in the white matter or granule-cell layer resulted in an all-or-none synaptic current as a result of climbing-fibre activation. Stimulation in the molecular layer caused a graded synaptic current, as expected for activation of parallel fibres. When the parallel fibres were stimulated twice at an interval of 40 ms, the second EPSC was facilitated; similar paired-pulse stimulation of the climbing fibre resulted in a depression of the second EPSC. Both parallel-fibre and climbing-fibre responses exhibited linear current-voltage relations. At a holding potential of -40 mV or in the nominal absence of Mg2+ these synaptic responses were unaffected by the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid (APV), but were blocked by the non-NMDA receptor antagonist 6-cyano-2,3-dihydro-7-nitroquinoxalinedione (CNQX). NMDA applied to the bath failed to evoke an inward current, whereas aspartate or glutamate induced a substantial current; this current was, however, largely reduced by CNQX, indicating that non-NMDA receptors mediate this response. These results indicate that both types of excitatory input to adult Purkinje cells are mediated exclusively by glutamate receptors of the non-NMDA type, and that these cells entirely lack NMDA receptors.     

Neuronal 5-hydroxytryptamine receptors outside the central nervous system

5-HT receptors are present on many types of neurone in the peripheral nervous system (PNS), e.g. sympathetic, parasympathetic, enteric and sensory cells, and mediate complex effects. These include depolarization, cell discharge and facilitation or depression of transmission. If 5-HT receptors can be classified according to the membrane mechanism associated with them, following the system adopted for mollusc neurones, such a classification would have to take into account two kinds of presynaptic and at least four kinds of postsynaptic action. Recent work suggests that a small number of analogues of 5-HT (tryptamine, 5-MOT, LSD) and antagonists (cocaine, methysergide, quipazine) may be useful in differentiating the various kinds of 5-HT receptor in the PNS. It is suggested that no single feature should be relied upon to characterize the receptors; classification might be based on consideration of function, evidence of tachyphylaxis, sensitivity to methysergide, cocaine, etc. On this basis, it is tentatively concluded that there are two kinds of 5-HT receptor mediating excitation in the PNS, neither of which can sensibly be termed an ‘M’ receptor. An interim form of terminology is proposed which makes use of an acronym of the distinctive features. A receptor mediating (E)xcitation, which shows (T)achyphylaxis, is (M)ethysergide (I)nsensitive but is blocked by (C)ocaine might be designated a 5-HT_ETMIC receptor, while a second which differs because it is insensitive to cocaine but activated by (F)ive-methoxytryptamine might be designated a 5-HT_ETMIF receptor. Amongst receptors mediating (I)nhibition, the best characterized is one mediating decreased transmitter release and activated by (L)SD. The term 5-HT_IL receptor is proposed. A second, post-synaptic inhibitory receptor is likely, but has not been adequately characterized at present.     

Long-term potentiation in cultured hippocampal neurons

Studies performed on low-density primary neuronal cultures have enabled dissection of molecular and cellular changes during N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP). Various electrophysiological and chemical induction protocols were developed for the persistent enhancement of excitatory synaptic transmission in hippocampal neuronal cultures. The characterisation of these plasticity models confirmed that they share many key properties with the LTP of CA1 neurons, extensively studied in hippocampal slices using electrophysiological techniques. For example, LTP in dissociated hippocampal neuronal cultures is also dependent on Ca(2+) influx through post-synaptic NMDA receptors, subsequent activation and autophosphorylation of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and an increase in alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor insertion at the post-synaptic membrane. The availability of models of LTP in cultured hippocampal neurons significantly facilitated the monitoring of changes in endogenous postsynaptic receptor proteins and the investigation of the associated signalling mechanisms that underlie LTP. A central feature of LTP of excitatory synapses is the recruitment of AMPA receptors at the postsynaptic site. Results from the use of cell culture-based models started to establish the mechanism by which synaptic input controls a neuron's ability to modify its synapses in LTP. This review focuses on key features of various LTP induction protocols in dissociated hippocampal neuronal cultures and the applications of these plasticity models for the investigation of activity-induced changes in native AMPA receptors.     

A biological model of the excitation of a second order sensory neurone

Summary Computer simulation of a relatively simple model can reproduce the main characteristics of the firing patters of some nerve cells. The abdominal stretch receptor of the crayfish has provided an analogous biological model. Synaptic input impulses were simulated by randomly distributed, short lasting transmembrane current pulses. Under these experimental conditions the stretch receptor neurone largely behaved as predicted by the computer simulations.     

The self-tuning neuron: synaptic scaling of excitatory synapses

Homeostatic synaptic scaling is a form of synaptic plasticity that adjusts the strength of all of a neuron's excitatory synapses up or down to stabilize firing. Current evidence suggests that neurons detect changes in their own firing rates through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of glutamate receptors at synaptic sites. Additional mechanisms may allow local or network-wide changes in activity to be sensed through parallel pathways, generating a nested set of homeostatic mechanisms that operate over different temporal and spatial scales.