Biomedical subjects

A Destexhe

Publications and source records attributed to A Destexhe.

At least 19 recordsLinked to original sources

PubMed1998

Spike-and-wave oscillations based on the properties of GABAB receptors.

Neocortical and thalamic neurons are involved in the genesis of generalized spike-and-wave (SW) epileptic seizures. The cellular mechanism of SW involves complex interactions between intrinsic neuronal firing properties and multiple types of synaptic receptors, but because of the complexity of these interactions the exact details of this mechanism are unclear. In this paper these types of interactions were investigated by using biophysical models of thalamic and cortical neurons. It is shown first that, because of the particular activation properties of GABAB receptor-mediated responses, simulated field potentials can display SW waveforms if cortical pyramidal cells and interneurons generate prolonged discharges in synchrony, without any other assumptions. Here the "spike" component coincided with the synchronous firing, whereas the "wave" component was generated mostly by slow GABAB-mediated K+ currents. Second, the model suggests that intact thalamic circuits can be forced into a approximately 3 Hz oscillatory mode by corticothalamic feedback. Here again, this property was attributable to the characteristics of GABAB-mediated inhibition. Third, in the thalamocortical system this property can lead to generalized approximately 3 Hz oscillations with SW field potentials. The oscillation consisted of a synchronous prolonged firing in all cell types, interleaved with a approximately 300 msec period of neuronal silence, similar to experimental observations during SW seizures. This model suggests that SW oscillations can arise from thalamocortical loops in which the corticothalamic feedback indirectly evokes GABAB-mediated inhibition in the thalamus. This mechanism is shown to be consistent with a number of different experimental models, and experiments are suggested to test its consistency.

Action Potentials↗

PubMed1998

Dendritic low-threshold calcium currents in thalamic relay cells.

The low-threshold calcium current (IT) underlies burst generation in thalamocortical (TC) relay cells and plays a central role in the genesis of synchronized oscillations by thalamic circuits. Here we have combined in vitro recordings and computational modeling techniques to investigate the consequences of dendritically located IT in TC cells. Simulations of a reconstructed TC cell were compared with the recordings obtained in the same cell to constrain the values of its passive parameters. T-current densities in soma and proximal dendrites were then estimated by matching the model to voltage-clamp recordings obtained in dissociated TC cells, which lack most of the dendrites. The distal dendritic T-current density was constrained by recordings in intact TC cells, which show 5-14 times larger peak T-current amplitudes compared with dissociated cells. Comparison of the model with the recordings of the same cell constrained further the T-current density in dendrites, which had to be 4.5-7.6 times higher than in the soma to reproduce all experimental results. Similar conclusions were reached using a simplified three-compartment model. Functionally, the model shows that the same amount of T-channels can lead to different bursting behaviors if they are exclusively somatic or distributed throughout the dendrites. In conclusion, this combination of models and experiments shows that dendritic T-currents are necessary to reproduce low-threshold calcium electrogenesis in TC cells. Dendritic T-current may also have significant functional consequences, such as an efficient modulation of thalamic burst discharges by corticothalamic feedback.

Action Potentials↗

PubMed1998

Inhibitory control of somatodendritic interactions underlying action potentials in neocortical pyramidal neurons in vivo: an intracellular and computational study.

The effect of synaptic inputs on somatodendritic interactions during action potentials was investigated, in the cat, using in vivo intracellular recording and computational models of neocortical pyramidal cells. An array of 10 microelectrodes, each ending at a different cortical depth, was used to preferentially evoke synaptic inputs to different somatodendritic regions. Relative to action potentials evoked by current injection, spikes elicited by cortical microstimuli were reduced in amplitude and duration, with stimuli delivered at proximal (somatic) and distal (dendritic) levels evoking the largest and smallest decrements, respectively. When the inhibitory postsynaptic potential reversal was shifted to around -50 mV by recording with KCl pipettes, synaptically-evoked spikes were significantly less reduced than with potassium acetate or cesium acetate pipettes, suggesting that spike decrements are not only due to a shunt, but also to voltage-dependent effects. Computational models of neocortical pyramidal cells were built based on available data on the distribution of active currents and synaptic inputs in the soma and dendrites. The distribution of synapses activated by extracellular stimulation was estimated by matching the model to experimental recordings of postsynaptic potentials evoked at different depths. The model successfully reproduced the progressive spike amplitude reduction as a function of stimulation depth, as well as the effects of chloride and cesium. The model revealed that somatic spikes contain an important contribution from proximal dendritic sodium currents up to approximately 100 microm and approximately 300 microm from the soma under control and cesium conditions, respectively. Proximal inhibitory postsynaptic potentials can present this dendritic participation thus reducing the spike amplitude at the soma. The model suggests that the somatic spike amplitude and shape can be used as a "window" to infer the electrical participation of proximal dendrites. Thus, our results suggest that inhibitory postsynaptic potentials can control the participation of proximal dendrites in somatic sodium spikes.

Action Potentials↗

PubMed1998

Mechanisms underlying the synchronizing action of corticothalamic feedback through inhibition of thalamic relay cells.

Early studies have shown that spindle oscillations are generated in the thalamus and are synchronized over wide cortical territories. More recent experiments have shown that this large-scale synchrony depends on the integrity of corticothalamic feedback. Previously proposed mechanisms emphasized exclusively intrathalamic mechanisms to generate the synchrony of these oscillations. In the present paper, we propose a cellular mechanism in which the synchrony is dependent of a mutual interaction between cortex and thalamus. This cellular mechanism is tested by computational models consisting of pyramidal cells, interneurons, thalamic reticular (RE) and thalamocortical (TC) relay cells, on the basis of voltage-clamp data on intrinsic currents and synaptic receptors present in the circuitry. The model suggests that corticothalamic feedback must operate on the thalamus mainly through excitation of GABAergic RE neurons, therefore recruiting relay cells essentially through inhibition and rebound. We provide experimental evidence for such dominant inhibition in the lateral posterior nucleus. In these conditions, the model shows that cortical discharges optimally evoked thalamic oscillations. This feature is essential to the present cellular mechanism and is also consistently observed experimentally. The model further shows that, with this type of corticothalamic feedback, cortical discharges recruited large areas of the thalamus because of the divergent cortex-to-RE and RE-to-TC axonal projections. Consequently, the thalamocortical network generated patterns of oscillations and synchrony similar to in vivo recordings. The model also emphasizes the important role of the modulation of the Ih current by calcium in TC cells. This property conferred a relative refractoriness to the entire network, a feature also observed experimentally, as we show here. Further, the same property accounted for various spatiotemporal features of oscillations, such as systematic propagation after low-intensity cortical stimulation, local oscillations, and more generally, a high variability in the patterns of spontaneous oscillations, similar to in vivo recordings. We propose that the large-scale synchrony of spindle oscillations in vivo is the result of thalamocortical interactions in which the corticothalamic feedback acts predominantly through the RE nucleus. Several predictions are suggested to test the validity of this model.

Animals↗

PubMed1998

Impact of spontaneous synaptic activity on the resting properties of cat neocortical pyramidal neurons In vivo.

The frequency of spontaneous synaptic events in vitro is probably lower than in vivo because of the reduced synaptic connectivity present in cortical slices and the lower temperature used during in vitro experiments. Because this reduction in background synaptic activity could modify the integrative properties of cortical neurons, we compared the impact of spontaneous synaptic events on the resting properties of intracellularly recorded pyramidal neurons in vivo and in vitro by blocking synaptic transmission with tetrodotoxin (TTX). The amount of synaptic activity was much lower in brain slices (at 34 degrees C), as the standard deviation of the intracellular signal was 10-17 times lower in vitro than in vivo. Input resistances (Rins) measured in vivo during relatively quiescent epochs ("control Rins") could be reduced by up to 70% during periods of intense spontaneous activity. Further, the control Rins were increased by approximately 30-70% after TTX application in vivo, approaching in vitro values. In contrast, TTX produced negligible Rin changes in vitro (approximately 4%). These results indicate that, compared with the in vitro situation, the background synaptic activity present in intact networks dramatically reduces the electrical compactness of cortical neurons and modifies their integrative properties. The impact of the spontaneous synaptic bombardment should be taken into account when extrapolating in vitro findings to the intact brain.

Animals↗

PubMed1997

Conductance-based integrate-and-fire models.

A conductance-based model of Na+ and K+ currents underlying action potential generation is introduced by simplifying the quantitative model of Hodgkin and Huxley (HH). If the time course of rate constants can be approximated by a pulse, HH equations can be solved analytically. Pulse-based (PB) models generate action potentials very similar to the HH model but are computationally faster. Unlike the classical integrate-and-fire (IAF) approach, they take into account the changes of conductances during and after the spike, which have a determinant influence in shaping neuronal responses. Similarities and differences among PB, IAF, and HH models are illustrated for three cases: high-frequency repetitive firing, spike timing following random synaptic inputs, and network behavior in the presence of intrinsic currents.

Action Potentials↗

PubMed1997

Spatiotemporal patterns of spindle oscillations in cortex and thalamus.

Spindle oscillations (7-14 Hz) appear in the thalamus and cortex during early stages of sleep. They are generated by the combination of intrinsic properties and connectivity patterns of thalamic neurons and distributed to cortical territories by thalamocortical axons. The corticothalamic feedback is a major factor in producing coherent spatiotemporal maps of spindle oscillations in widespread thalamic territories. Here we have investigated the spatiotemporal patterns of spontaneously occurring and evoked spindles by means of multisite field potential and unit recordings in intact cortex and decorticated animals. We show that (1) spontaneous spindle oscillations are synchronized over large cortical areas during natural sleep and barbiturate anesthesia; (2) under barbiturate anesthesia, the cortical coherence is not disrupted by transection of intracortical synaptic linkages; (3) in intact cortex animals, spontaneously occurring barbiturate spindle sequences occur nearly simultaneously over widespread thalamic territories; (4) in the absence of cortex, the spontaneous spindle oscillations throughout the thalamus are less organized, but the local coherence (within 2-4 mm) is still maintained; and (5) spindling propagation is observed in intact cortex animals only when elicited by low intensity cortical stimulation, applied shortly before the initiation of a spontaneous spindle sequence; propagation velocities are between 1 and 3 mm/sec, measured in the anteroposterior axis of the thalamus; increasing the intensity of cortical stimulation triggers spindle oscillations, which start simultaneously in all leads. We propose that, in vivo, the coherence of spontaneous spindle oscillations in corticothalamic networks is attributable to the combined action of continuous background corticothalamic input initiating spindle sequences in several thalamic sites at the same time and divergent corticothalamic and intrathalamic connectivity.

Anesthesia↗

PubMed1997

Spindle oscillations during cortical spreading depression in naturally sleeping cats.

Spindling activity characterizes the EEG of animals and humans in the early stages of resting sleep. Spindles are defined as waxing and waning rhythmic waves at 7-14 Hz that recur periodically every 3-10 s. Spindling originates in the thalamus, but a role for the cerebral cortex in triggering and synchronizing thalamic spindles was shown by stimulation of the contralateral cortex avoiding antidromic activation of thalamocortical axons and by diminished coherency of thalamic spindles after hemidecortication. Spontaneous spindles under barbiturate anesthesia are waxing and waning but under ketamine-xylazine anesthesia or when evoked by strong stimuli spindle waves are almost exclusively waning, i.e. they start with maximum amplitude and then decrease progressively. Waxing and waning of spindles has been ascribed to progressive entrainment of units into the oscillation followed by a progressive desynchronization. Therefore, exclusively waning spindles would be produced by an initial high synchrony in the corticothalamic network. Such a situation is observable upon strong stimulation or, spontaneously, when spindles are paced by the slow cortical oscillation and preceded by a strong corticothalamic drive. We have conducted experiments in naturally sleeping cats to verify the occurrence of two patterns of spindle oscillations and to test the role of the cortex in synchronizing and shaping spindles. We have found that indeed two types of spindles (waxing and waning or mostly waning) occur in naturally sleeping animals. We also demonstrate that during cortical spreading depression spindles are less synchronous and only of the waxing and waning type. As cortical activity recovers, waning spindles reappear and are preceded by electroencephalogram deflections which are related to corticothalamic depolarizing inputs. Our results strongly support the hypothesis of the role of the cerebral cortex in shaping and synchronizing thalamically generated spindles.

Animals↗

PubMed1997

Dynamic interactions determine partial thalamic quiescence in a computer network model of spike-and-wave seizures.

In vivo intracellular recording from cat thalamus and cortex was performed during spontaneous spike-wave seizures characterized by synchronously firing cortical neurons correlated with the electroencephalogram. During these seizures, thalamic reticular (RE) neurons discharged with long spike bursts riding on a depolarization, whereas thalamocortical (TC) neurons were either entrained into the seizures (40%) or were quiescent (60%). During quiescence, TC neurons showed phasic inhibitory postsynaptic potentials (IPSPs) that coincided with paroxysmal depolarizing shifts in the simultaneously recorded cortical neuron. Computer simulations of a reciprocally connected TC-RE pair showed two major modes of TC-RE interaction. In one mode, a mutual oscillation involved direct TC neuron excitation of the RE neuron leading to a burst that fed back an IPSP into the TC neuron, producing a low-threshold spike. In the other, quiescent mode, the TC neuron was subject to stronger coalescing IPSPs. Simulated cortical stimulation could trigger a transition between the two modes. This transition could go in either direction and was dependent on the precise timing of the input. The transition did not always follow the stimulation immediately. A larger, multicolumnar simulation was set up to assess the role of the TC-RE pair in the context of extensive divergence and convergence. The amount of TC neuron spiking generally correlated with the strength of total inhibitory input, but large variations in the amount of spiking could be seen. Evidence for mutual oscillation could be demonstrated by comparing TC neuron firing with that in reciprocally connected RE neurons. An additional mechanism for TC neuron quiescence was assessed with the use of a cooperative model of gamma-aminobutyric acid-B (GABA(B))-mediated responses. With this model, RE neurons receiving repeated strong excitatory input produced TC neuron quiescence due to burst-duration-associated augmentation of GABA(B) current. We predict the existence of spatial inhomogeneity in apparently generalized spike-wave seizures, involving a center-surround pattern. In the center, intense cortical and RE neuron activity would be associated with TC neuron quiescence. In the surround, less intense hyperpolarization of TC neurons would allow low-threshold spikes to occur. This surround, an "epileptic penumbra," would be the forefront of the expanding epileptic wave during the process of initial seizure generalization. Therapeutically, we would then predict that agents that reduce TC neuron activity would have a greater effect on seizure onset than on ongoing spike-wave seizures or other thalamic oscillations.

Action Potentials↗

PubMed1997

Intracellular and computational characterization of the intracortical inhibitory control of synchronized thalamic inputs in vivo.

We investigated the presence and role of local inhibitory cortical control over synchronized thalamic inputs during spindle oscillations (7-14 Hz) by combining intracellular recordings of pyramidal cells in barbiturate-anesthetized cats and computational models. The recordings showed that 1) similar excitatory postsynaptic potential (EPSP)/inhibitory postsynaptic potential (IPSP) sequences occurred either during spindles or following thalamic stimulation; 2) reversed IPSPs with chloride-filled pipettes transformed spindle-related EPSP/IPSP sequences into robust bursts with spike inactivation, resembling paroxysmal depolarizing shifts during seizures; and 3) dual simultaneous impalements showed that inhibition associated with synchronized thalamic inputs is local. Computational models were based on reconstructed pyramidal cells constrained by recordings from the same cells. These models showed that the transformation of EPSP/IPSP sequences into fully developed spike bursts critically needs a relatively high density of inhibitory currents in the soma and proximal dendrites. In addition, models predict significant Ca2+ transients in dendrites due to synchronized thalamic inputs. We conclude that synchronized thalamic inputs are subject to strong inhibitory control within the cortex and propose that 1) local impairment of inhibition contributes to the transformation of spindles into spike-wave-type discharges, and 2) spindle-related inputs trigger Ca2+ events in cortical dendrites that may subserve plasticity phenomena during sleep.

Animals↗

PubMed1996

Control of spatiotemporal coherence of a thalamic oscillation by corticothalamic feedback.

The mammalian thalamus is the gateway to the cortex for most sensory modalities. Nearly all thalamic nuclei also receive massive feedback projections from the cortical region to which they project. In this study, the spatiotemporal properties of synchronized thalamic spindle oscillations (7 to 14 hertz) were investigated in barbiturate-anesthetized cats, before and after removal of the cortex. After complete ipsilateral decortication, the long-range synchronization of thalamic spindles in the intact cortex hemisphere changed into disorganized patterns with low spatiotemporal coherence. Local thalamic synchrony was still present, as demonstrated by dual intracellular recordings from nearby neurons. In the cortex, synchrony was insensitive to the disruption of horizontal intracortical connections. These results indicate that the global coherence of thalamic oscillations is determined by corticothalamic projections.

Anesthesia↗

PubMed1996

Control of slow oscillations in the thalamocortical neuron: a computer model.

We investigated computer models of a single thalamocortical neuron to assess the interaction of intrinsic voltage-sensitive channels and cortical synaptic input in producing the range of oscillation frequencies observed in these cells in vivo. A morphologically detailed model with Hodgkin-Huxley-like ion channels demonstrated that intrinsic properties would be sufficient to readily produce 3 to 6 Hz oscillations. Hyperpolarization of the model cell reduced its oscillation frequency monotonically whether through current injection or modulation of a potassium conductance, simulating the response to a neuromodulatory input. We performed detailed analysis of highly reduced models to determine the mechanism of this frequency control. The interburst interval was controlled by two different mechanisms depending on whether or not the pacemaker current, IH, was present. In the absence of IH, depolarization during the interburst interval occurred at the same rate with different current injections. The voltage difference from the nadir to threshold for the low-threshold calcium current, IT, determined the interburst interval. In contrast, with IH present, the rate of depolarization depended on injected current. With the full model, simulated repetitive cortical synaptic input entrained oscillations up to approximately double the natural frequency. Cortical input readily produced phase resetting as well. Our findings suggest that neither ascending brainstem control altering underlying hyperpolarization, nor descending drive by repetitive cortical inputs, would alone be sufficient to produce the range of oscillation frequencies seen in thalamocortical neurons. Instead, intrinsic neuronal mechanisms would dominate for generating the delta range (0.5-4 Hz) oscillations seen during slow wave sleep, whereas synaptic interactions with cortex and the thalamic reticular nucleus would be required for faster oscillations in the frequency range of spindling (7-14 Hz).

Cerebral Cortex↗

PubMed1996

Ionic mechanisms underlying synchronized oscillations and propagating waves in a model of ferret thalamic slices.

1. A network model of thalamocortical (TC) and thalamic reticular (RE) neurons was developed based on electrophysiological measurements in ferret thalamic slices. Single-compartment TC and RE cells included voltage- and calcium-sensitive currents described by Hodgkin-Huxley type of kinetics. Synaptic currents were modeled by kinetic models of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), gamma-aminobutyric acid-A (GABAA) and GABAB receptors. 2. The model reproduced successfully the characteristics of spindle and slow bicuculline-induced oscillations observed in vitro. The characteristics of these two types of oscillations depended on both the intrinsic properties of TC and RE cells and their pattern of interconnectivity. 3. The oscillations were organized by the reciprocal recruitment between TC and RE cells, due to their manual connectivity and bursting properties. TC cells elicited AMPA-mediated excitatory postsynaptic potentials (EPSPs) in RE cells, whereas RE cells elicited a mixture of GABAA and GABAB inhibitory postsynaptic potentials (IPSPs) in TC cells. Because of the presence of a T current, sufficiently strong EPSPs could elicit a burst in RE cells, and TC cells could generate a rebound burst following GABAergic IPSPs. Under these conditions, interaction between the TC and RE cells produced sustained oscillations. 4. In the absence of spontaneous oscillation in any cell, the TC-RE network remained quiescent. Spindle oscillations with a frequency of 9-11 Hz could be initiated by stimulation of either TC or RE neurons. A few spontaneously oscillating TC neurons recruited the entire network model into a "waxing-and waning" oscillation. These "initiator" cells could be an extremely small proportion of TC cells. 5. In intracellular recordings, TC cells display a reduced ability for burst firing after a sequence of bursts. The "waning" phase of spindles was reproduced in the network model by assuming an activity-dependent upregulation of Ih operating via a calcium-binding protein in TC cells, as shown previously in a two-cell model. 6. Following the global suppression of GABAA inhibition, the disinhibited RE cells produced prolonged burst discharges that elicited strong GABAB-mediated currents in TC cells. The enhancement of slow IPSPs in TC cells was also due to cooperativity in the activation of GABAB-mediated current. These slow IPSPs recruited TC and RE cells into slower waxing-and-waning oscillations (3-4 HZ) that were even more highly synchronized. 7. Local axonal arborization of the TC to RE and RE to TC projections allowed oscillations to propagate through the network. An oscillation starting at a single focus induced a propagating wavefront as more cells were recruited progressively. The waning of the oscillation also propagated due to upregulation of Ih in TC cells, leading to waves of spindle activity as observed in experiments. 8. The spatiotemporal properties of propagating waves in the model were highly dependent on the intrinsic properties of TC cells. The spatial pattern of spiking activity was markedly different for spindles compared with bicuculline-induced oscillations and depended on the rebound burst behavior of TC cells. The upregulation of Ih produced a refractory period so that colliding spindle waves merged into a single oscillation and extinguished. Finally, reducing the Ih conductance led to sustained oscillations. 9. Two key properties of cells in the thalamic network may account for the initiation, propagation, and termination of spindle oscillations, the activity-dependent upregulation of Ih in TC cells, and the localized axonal projections between TC and RE cells. In addition, the model predicts that a nonlinear stimulus dependency of GABAB responses accounts for the genesis of prolonged synchronized discharges following block of GABAA receptors.

Animals↗

PubMed1996

In vivo, in vitro, and computational analysis of dendritic calcium currents in thalamic reticular neurons.

Thalamic reticular (RE) neurons are involved in the genesis of synchronized thalamocortical oscillations, which depend in part on their complex bursting properties. We have investigated the intrinsic properties of RE cells using computational models based on morphological and electrophysiological data. Simulations of a reconstructed RE cells were compared directly with recordings from the same cell to obtain precise values for the passive parameters. In a first series of experiments, the low-threshold calcium current (I(Ts)) was studied via voltage clamp in acutely dissociated RE cells that lack most of their dendrites. Simulations based on a cell with truncated dendrites and Hodgkin-Huxley kinetics reproduced these recordings with a relatively low density of I(Ts). In a second series of experiments, voltage-clamp recordings obtained in intact RE cells in slices showed a higher amplitude and slower kinetics of I(Ts). These properties could be reproduced from the reconstructed cell model assuming higher densities of I(Ts) in distal dendrites. In a third series of experiments, current-clamp recordings were obtained on RE cells in vivo. The marked differences with in vitro recordings could be reconciled by simulating synaptic bombardment in the dendrites of RE cells, but only if they contained high distal densities of I(Ts). In addition, simpler models with as few as three compartments could reproduce the same behavior assuming dendritic I(Ts). These models and experiments show how intrinsic bursting properties of RE cells, as recorded in vivo and in vitro, may be explained by dendritic calcium currents.

Animals↗

PubMed1995

G protein activation kinetics and spillover of gamma-aminobutyric acid may account for differences between inhibitory responses in the hippocampus and thalamus.

We have developed a model of gamma-aminobutyric acid (GABA)ergic synaptic transmission mediated by GABAA and GABAB receptors, including cooperativity in the guanine nucleotide binding protein (G protein) cascade mediating the activation of K+ channels by GABAB receptors. If the binding of several G proteins is needed to activate the K+ channels, then only a prolonged activation of GABAB receptors evoked detectable currents. This could occur if strong stimuli evoked release in adjacent terminals and the spillover resulted in prolonged activation of the receptors, leading to inhibitory responses similar to those observed in hippocampal slices. The same model also reproduced thalamic GABAB responses to high-frequency bursts of stimuli. In this case, prolonged activation of the receptors was due to high-frequency release conditions. This model provides insights into the function of GABAB receptors in normal and epileptic discharges.

GTP-Binding Proteins↗

PubMed1994

Modeling the control of reticular thalamic oscillations by neuromodulators.

Compartmental models of thalamic reticular (RE) neurons were investigated based on current-clamp and voltage-clamp data. Spontaneous oscillations in the model arise from the interaction between inhibitory synaptic currents and the rebound burst of RE cells. These oscillations critically depend on the level of the resting membrane potential. A network of RE neurons can be switched between silent and sustained oscillatory behavior by modulating a leak potassium current through neuromodulatory synapses. These results suggest that neuromodulators, such as noradrenaline, serotonin and glutamate, can exert a decisive control over the oscillatory activity of systems of RE cells. The model may explain why the isolated RE nucleus oscillates spontaneously in vivo but not in vitro.

Electrophysiology↗

PubMed1994

Synthesis of models for excitable membranes, synaptic transmission and neuromodulation using a common kinetic formalism.

Markov kinetic models were used to synthesize a complete description of synaptic transmission, including opening of voltage-dependent channels in the presynaptic terminal, release of neurotransmitter, gating of postsynaptic receptors, and activation of second-messenger systems. These kinetic schemes provide a more general framework for modeling ion channels than the Hodgkin-Huxley formalism, supporting a continuous spectrum of descriptions ranging from the very simple and computationally efficient to the highly complex and biophysically precise. Examples are given of simple kinetic schemes based on fits to experimental data that capture the essential properties of voltage-gated, synaptic and neuromodulatory currents. The Markov formalism allows the dynamics of ionic currents to be considered naturally in the larger context of biochemical signal transduction. This framework can facilitate the integration of a wide range of experimental data and promote consistent theoretical analysis of neural mechanisms from molecular interactions to network computations.

Animals↗

PubMed1994

A model of spindle rhythmicity in the isolated thalamic reticular nucleus.

1. The oscillatory properties of the isolated reticular (RE) thalamus were modeled with the use of compartmental models of RE cells. Hodgkin-Huxley type kinetic models of ionic channels were derived from voltage- and current-clamp data from RE cells. Interactions between interconnected RE cells were simulated with the use of a kinetic model of gamma-aminobutyric acid (GABA) inhibitory synapses. 2. The intrinsic bursting properties of RE cells in the model were due to the presence of a low-threshold Ca2+ current and two Ca(2+)-activated currents. The properties of these model RE cells were compared with RE neurons recorded intracellularly in vivo in cats. 3. Model RE cells densely interconnected with GABAA synapses produced synchronous oscillations at a frequency close to that of spindles (7-14 Hz). Networks of RE neurons organized in a two-dimensional array with only proximal connectivity also exhibited synchronized oscillations in the spindle range. In addition, the proximally connected network showed periods of high and low synchronicity, giving rise to waxing and waning oscillations in the population of RE cells. 4. The spatiotemporal behavior of the network was investigated during waxing and waning oscillations. The waxing and waning emerged as an alternation between periods of desynchronized and synchronized activity, corresponding to periods of irregular and coherent spatial activity. During synchronized periods, the network displayed propagating coherent waves of synchronous activity that had a tendency to form spirals. 5. Networks of model RE neurons fully connected through GABAB synapses exhibited perfectly synchronous oscillations at lower frequencies (0.5-1 Hz), but two-dimensional networks with proximal GABAB connectivity failed to synchronize. 6. These simulations demonstrate that networks of model neurons that include the main intrinsic currents found in RE cells can generate waxing and waning oscillatory activity similar to the spindle rhythmicity observed in the isolated RE nucleus in vivo. The model reveals the interplay between the intrinsic rhythmic properties of RE cells and the fast synaptic interactions in organizing synchronized rhythmicity.

Afferent Pathways↗