It is widely accepted that corticothalamic neurons recruit the thalamus in slow oscillation, but global slow-wave thalamocortical dynamics have never been experimentally shown. We analyzed intracellular activities of neurons either from different cortical areas or from a variety of specific and nonspecific thalamic nuclei in relation to the phase of global EEG signal in ketamine-xylazine anesthetized mice. We found that, on average, slow-wave active states started off within frontal cortical areas as well as higher-order and intralaminar thalamus (posterior and parafascicular nuclei) simultaneously. Then, the leading edge of active states propagated in the anteroposterior/lateral direction over the cortex at ∼40 mm/s. The latest structure we recorded within the slow-wave cycle was the anterior thalamus, which followed active states of the retrosplenial cortex. Active states from different cortical areas tended to terminate simultaneously. Sensory thalamic ventral posterior medial and lateral geniculate nuclei followed cortical active states with major inhibitory and weak tonic-like “modulator” EPSPs. In these nuclei, sharp-rising, large-amplitude EPSPs (“drivers”) were not modulated by cortical slow waves, suggesting their origin in ascending pathways. The thalamic active states in other investigated nuclei were composed of depolarization: some revealing “driver”- and “modulator”-like EPSPs, others showing “modulator”-like EPSPs only. We conclude that sensory thalamic nuclei follow the propagating cortical waves, whereas neurons from higher-order thalamic nuclei display “hub dynamics” and thus may contribute to the generation of cortical slow waves.
cortex; dynamics; intracellular; slow oscillation; thalamus
Slow oscillation is the main brain rhythm observed during deep sleep in mammals. Although several studies have demonstrated its neocortical origin, the extent of the thalamic contribution is still a matter of discussion. Using electrophysiological recordings in vivo on cats and computational modeling, we found that the local thalamic inactivation or the complete isolation of the neocortical slabs maintained within the brain dramatically reduced the expression of slow and fast oscillations in affected cortical areas. The slow oscillation began to recover 12 h after thalamic inactivation. The slow oscillation, but not faster activities, nearly recovered after 30 h and persisted for weeks in the isolated slabs. We also observed an increase of the membrane potential fluctuations recorded in vivo several hours after thalamic inactivation. Mimicking this enhancement in a network computational model with an increased postsynaptic activity of long-range intracortical afferents or scaling K+ leak current, but not several other Na+ and K+ intrinsic currents was sufficient for recovering the slow oscillation. We conclude that, in the intact brain, the thalamus contributes to the generation of cortical active states of the slow oscillation and mediates its large-scale synchronization. Our study also suggests that the deafferentation-induced alterations of the sleep slow oscillation can be counteracted by compensatory intracortical mechanisms and that the sleep slow oscillation is a fundamental and intrinsic state of the neocortex.
cortex; in vivo; model; plasticity; slow oscillation; thalamus
Neuronal synchronization occurs when two or more neuronal events are coordinated across time. Local synchronization produces field potentials. Long-range synchronization between distant brain sites contributes to the electroencephalogram. Neuronal synchronization depends on synaptic (chemical/electrical), ephaptic, and extracellular interactions. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at www.ncbi.nlm.nih.gov/books).
Epilepsy; Extracelullar conditions; Feedback loops; Local synchronization; Long-range synchronization; Oscillations; Propagating activities; Seizures
Parallel electrophysiological recording and behavioral monitoring of freely moving animals is essential for a better understanding of the neural mechanisms underlying behavior. In this paper we describe a novel wireless recording technique, which is capable of synchronously recording in vivo multichannel electrophysiological (LFP, MUA, EOG, EMG) and activity data (accelerometer, video) from freely moving cats. The method is based on the integration of commercially available components into a simple monitoring system and is complete with accelerometers and the needed signal processing tools. LFP activities of freely moving group-housed cats were recorded from multiple intracortical areas and from the hippocampus. EMG, EOG, accelerometer and video were simultaneously acquired with LFP activities 24-h a day for 3 months. These recordings confirm the possibility of using our wireless method for 24-h long-term monitoring of neurophysiological and behavioral data of freely moving experimental animals such as cats, ferrets, rabbits and other large animals.
Electrophysiology; movement; accelerometer; sleep/wake
The stereotaxic reference marks of ferret skull have large variability and the reference point for stereotaxic experiments in ferret brain is difficult to define. Here, using extracellular single-unit recordings, we studied the somatotopic organization of cutaneous receptive fields in the ventroposterior medial (VPM) and the ventral posterolateral (VPL) nuclei of the ferret thalamus. The mechanical stimulation of the skin was done through air puffs. The skull was positioned according to Horsley-Clarke coordinate system. Most of the neurons responding to face skin stimulation were located +7–+9 mm anterior, 2–3.9 mm lateral and 7–9.6 mm from cortical surface, whereas those responding to body skin stimulation were located +7–+10 mm anterior, 3.3–5.5 mm lateral and 6.7–10 mm from cortical surface. Out of 90 thalamic neurons recorded in this study, 58 responded to the body and the other neurons to the face stimulation. All neurons responded with spikes to stimulus onset, 37% of neurons responded only to stimuli onset and offset and 22% neurons fired tonically throughout stimulating epoch. The whiskers representation was located in the middle of the VPM nucleus, whereas those of the tongue, nose, bridge of the nose, supraorbital areas, upper and lower lips, and lower jaw were surrounding the whiskers representation. Within the VPL nucleus there was a clear topological correspondence from forelimb to hindlimb in the medial-to-lateral direction. Our findings indicate the whiskers representation in VPM or the forelimb-hindlimb representation in the VPL nucleus can be considered as a reliable reference in the ferret thalamus.
thalamus; VPM; VPL; ferret; tactile stimulus
Long-term plasticity contributes to memory formation and sleep plays a critical role in memory consolidation. However, it is unclear whether sleep slow oscillation by itself induces long-term plasticity that contributes to memory retention. Using in vivo pre-thalamic electrical stimulation at 1 Hz which itself does not induce immediate potentiation of evoked responses, we investigated how the cortical evoked response was modulated by different states of vigilance. We found that somatosensory evoked potentials during wake were enhanced after a slow-wave sleep episode (with or without stimulation during sleep) as compared to a previous wake episode. In vitro, we determined that this enhancement has a postsynaptic mechanism that is calcium-dependent, requires hyperpolarization periods (slow waves), and requires a co-activation of both AMPA and NMDA receptors. Our results suggest that long-term potentiation occurs during slow-wave sleep supporting its contribution to memory.
Trauma and brain infection are the primary sources of acquired epilepsy, which can occur at any age and may account for a high incidence of epilepsy in developing countries. We have explored the hypothesis that penetrating cortical wounds cause deafferentation of the neocortex, which triggers homeostatic plasticity and lead to epileptogenesis (Houweling etal., 2005). In partial deafferentation experiments of adult cats, acute seizures occurred in most preparations and chronic seizures occurred weeks to months after the operation in 65% of the animals (Nita etal., 2006,2007; Nita and Timofeev, 2007). Similar deafferentation of young cats (age 8–12 months) led to some acute seizures, but we never observed chronic seizure activity even though there was enhanced slow-wave activity in the partially deafferented hemisphere during quiet wakefulness. This suggests that despite a major trauma, the homeostatic plasticity in young animals was able to restore normal levels of cortical excitability, but in fully adult cats the mechanisms underlying homeostatic plasticity may lead to an unstable cortical state. To test this hypothesis we made an undercut in the cortex of an elderly cat. After several weeks this animal developed seizure activity. These observations may lead to an intervention after brain trauma that prevents epileptogenesis from occurring in adults.
sleep; wake; trauma; excitability; epileptogenesis; seizure; epilepsy
Large amplitude slow waves are characteristic for the summary brain activity, recorded as electroencephalogram (EEG) or local field potentials (LFP), during deep stages of sleep and some types of anesthesia. Slow rhythm of the synchronized EEG reflects an alternation of active (depolarized, UP) and silent (hyperpolarized, DOWN) states of neocortical neurons. In neurons, involvement in the generalized slow oscillation results in a long-range synchronization of changes of their membrane potential as well as their firing. Here, we aimed at intracellular analysis of details of this synchronization. We asked which components of neuronal activity exhibit long-range correlations during the synchronized EEG? To answer this question, we made simultaneous intracellular recordings from two to four neocortical neurons in cat neocortex. We studied how correlated is the occurrence of active and silent states, and how correlated are fluctuations of the membrane potential in pairs of neurons located close one to the other or separated by up to 13 mm. We show that strong long-range correlation of the membrane potential was observed only (i) during the slow oscillation but not during periods without the oscillation, (ii) during periods which included transitions between the states but not during within-the-state periods, and (iii) for the low-frequency (<5 Hz) components of membrane potential fluctuations but not for the higher-frequency components (>10 Hz). In contrast to the neurons located several millimeters one from the other, membrane potential fluctuations in neighboring neurons remain strongly correlated during periods without slow oscillation. We conclude that membrane potential correlation in distant neurons is brought about by synchronous transitions between the states, while activity within the states is largely uncorrelated. The lack of the generalized fine-scale synchronization of membrane potential changes in neurons during the active states of slow oscillation may allow individual neurons to selectively engage in short living episodes of correlated activity—a process that may be similar to dynamical formation of neuronal ensembles during activated brain states.
intracellular recording; cat; sleep; synchrony
Deep anesthesia is commonly used as a model of slow-wave sleep (SWS). Ketamine-xylazine anesthesia reproduces the main features of sleep slow oscillation: slow, large amplitude waves in field potential, which are generated by the alternation of hyperpolarized and depolarized states of cortical neurons. However, direct quantitative comparison of field potential and membrane potential fluctuations during natural sleep and anesthesia is lacking, so it remains unclear how well the properties of sleep slow oscillation are reproduced by the ketamine-xylazine anesthesia model. Here, we used field potential and intracellular recordings in different cortical areas in the cat, to directly compare properties of slow oscillation during natural sleep and ketamine-xylazine anesthesia. During SWS cortical activity showed higher power in the slow/delta (0.1-4 Hz) and spindle (8-14 Hz) frequency range, while under anesthesia the power in the gamma band (30-100 Hz) was higher. During anesthesia, slow waves were more rhythmic and more synchronous across the cortex. Intracellular recordings revealed that silent states were longer and the amplitude of membrane potential around transition between active and silent states was bigger under anesthesia. Slow waves were largely uniform across cortical areas under anesthesia, but in SWS they were most pronounced in associative and visual areas, but smaller and less regular in somatosensory and motor cortices. We conclude that although the main features of the slow oscillation in sleep and anesthesia appear similar, multiple cellular and network features are differently expressed during natural SWS as compared to ketamine-xylazine anesthesia.
Sleep; oscillations; synchrony; intracellular; anesthesia; ketamine-Xylazine
Throughout life, thalamocortical (TC) network alternates between activated states (wake or rapid eye movement sleep) and slow oscillatory state dominating slow-wave sleep. The patterns of neuronal firing are different during these distinct states. I propose that due to relatively regular firing, the activated states preset some steady state synaptic plasticity and that the silent periods of slow-wave sleep contribute to a release from this steady state synaptic plasticity. In this respect, I discuss how states of vigilance affect short-, mid-, and long-term synaptic plasticity, intrinsic neuronal plasticity, as well as homeostatic plasticity. Finally, I suggest that slow oscillation is intrinsic property of cortical network and brain homeostatic mechanisms are tuned to use all forms of plasticity to bring cortical network to the state of slow oscillation. However, prolonged and profound shift from this homeostatic balance could lead to development of paroxysmal hyperexcitability and seizures as in the case of brain trauma.
sleep; wake; oscillations; synaptic transmission; synaptic plasticity; intrinsic plasticity
Seizures are associated with a reduction in extracellular Ca2+ concentration ([Ca2+]o) and an increase in extracellular K+ concentration ([K+]o). The long-range synchrony observed between distant electrodes during seizures is weak. We hypothesized that changes in extracellular ionic conditions during seizures are sufficient to alter synaptic neuronal responses and synchrony in the neocortex.
We obtained in vivo and in vitro electrophysiologic recordings combined with microstimulation from cat/rat neocortical neurons during seizures and seizure-like ionic conditions. In vitro the [K+]o was 2.8, 6.25, 8.0, and 12 mM and the [Ca2+]o was 1.2 and 0.6 mM.
During seizures recorded in vivo, we observed abolition of evoked synaptic responses. In vitro, the membrane potential of both regular-spiking and fast-spiking neurons was depolarized in high [K+]o conditions and hyperpolarized in high [Ca2+]o conditions. During high [K+]o conditions, changes in [Ca2+]o did not affect membrane potential. The synaptic responsiveness of both regular-spiking and fast-spiking neurons was reduced during seizure-like ionic conditions. A reduction in [Ca2+]o to 0.6 mM increased failure rates but did not abolish responses. However, an increase in [K+]o to 12 mM abolished postsynaptic responses, which depended on a blockade in axonal spike propagation.
We conclude that concomitant changes in [K+]o and [Ca2+]o observed during seizures contribute largely to the alterations of synaptic neuronal responses and to the decrease in long-range synchrony during neocortical seizures.
Cortex; Ions; Epilepsy; Excitability; Synaptic
Spindle oscillations are commonly observed during stage two of non-REM sleep. During sleep spindles, the cerebral cortex and thalamus interact through feedback connections. Both initiation and termination of spindle oscillations are thought to originate in the thalamus, based on thalamic recordings and computational models, although some in vivo results suggest otherwise. Here, we have used computer modeling and in vivo multisite recordings from the cortex and the thalamus in cats to examine the involvement of the cortex in spindle oscillations. We found that although the propagation of spindles depended on synaptic interaction within the thalamus, the initiation and termination of spindle sequences critically involved corticothalamic influences.
Acute cerebral cortical trauma often leads to paroxysmal activities which terminate in a few hours, but several months later, patients can develop epilepsy. The process occurring between the initial acute triggered seizures and the onset of spontaneous unprovoked seizures is termed epileptogenesis. Here we summarize recent morphological, electro-physiological and computational studies demonstrating that partial cortical isolation increases the number and duration of silent states in the cortical network, boosting neuronal connectivity and network excitability. These changes develop progressively, and after several weeks their synergetic action leads to epilepsy.
Sleep; wake; epilepsy; epileptogenesis; synaptic
Little is known about the dynamics and mechanisms of transitions between tonic firing and bursting in cortical networks. Here, we use a computational model of a neocortical circuit with extracellular potassium dynamics to show that activity-dependent modulation of intrinsic excitability can lead to sustained oscillations with slow transitions between two distinct firing modes: fast run (tonic spiking or fast bursts with few spikes) and slow bursting. These transitions are caused by a bistability with hysteresis in a pyramidal cell model. Balanced excitation and inhibition stabilizes a network of pyramidal cells and inhibitory interneurons in the bistable region and causes sustained periodic alternations between distinct oscillatory states. During spike-wave seizures, neocortical paroxysmal activity exhibits qualitatively similar slow transitions between fast run and bursting. We therefore predict that extracellular potassium dynamics can cause alternating episodes of fast and slow oscillatory states in both normal and epileptic neocortical networks.
neocortex; computational model; bistability; hysteresis; extracellular potassium concentration; paroxysmal activity
The thalamic reticular (RE) nucleus is a major source of inhibition in the thalamus. It plays a crucial role in regulating the excitability of thalamocortical networks and in generating some sleep rhythms. Current-clamp intracellular recordings of RE neurons in cats under barbiturate anesthesia revealed the presence of membrane bistability in ~20% of neurons. Bistability consisted of two alternate membrane potentials, separated by ~17–20 mV. While non-bistable (common) RE neurons fired rhythmic spike-bursts during spindles, bistable RE neurons fired tonically, with burst modulation, throughout spindle sequences. Bistability was strongly voltage dependent and only expressed under resting conditions (i.e. no current injection). The transition from the silent to the active state was a regenerative event that could be activated by brief depolarization, whereas brief hyperpolarizations could switch the membrane potential from the active to the silent state. These effects outlasted the current pulses. Corticothalamic stimulation could also switch the membrane potential from silent to active states. Addition of QX-314 in the recording micropipette either abolished or disrupted membrane bistability, suggesting INa(p) to be responsible for its generation. Thalamocortical cells presented various patterns of spindling that reflected the membrane bistability in RE neurons. Finally, experimental data and computer simulations predicted a role for RE neurons’ membrane bistability in inducing various patterns of spindling in target thalamocortical cells. We conclude that membrane bistability of RE neurons is an intrinsic property, likely generated by INa(p) and modulated by cortical influences, as well as a factor that determines different patterns of spindle rhythms in thalamocortical neurons.
Chronically isolated neocortex develops chronic hyperexcitability and focal epileptogenesis in a period of days to weeks. The mechanisms operating in this model of post-traumatic epileptogenesis are not well understood. We hypothesized that the spontaneous burst discharges recorded in chronically isolated neocortex result from homeostatic plasticity (a mechanism generally assumed to stabilize neuronal activity) induced by low neuronal activity after deafferentation. To test this hypothesis we constructed computer models of neocortex incorporating a biologically based homeostatic plasticity rule that operates to maintain firing rates. After deafferentation, homeostatic upregulation of excitatory synapses on pyramidal cells, either with or without concurrent downregulation of inhibitory synapses or upregulation of intrinsic excitability, initiated slowly repeating burst discharges that closely resembled the epileptiform burst discharges recorded in chronically isolated neocortex. These burst discharges lasted a few hundred ms, propagated at 1–3 cm/s and consisted of large (10–15 mV) intracellular depolarizations topped by a small number of action potentials. Our results support a role for homeostatic synaptic plasticity as a novel mechanism of post-traumatic epileptogenesis.
brain trauma; computational model; deafferentation; epilepsy; injury; slow oscillation
Thalamic reticular (RE) neurons are crucially implicated in brain rhythms. Here, we report that RE neurons of adult cats, recorded and stained intracellularly in vivo, displayed spontaneously occurring spikelets, which are characteristic of central neurons that are coupled electrotonically via gap junctions. Spikelets occurred spontaneously during spindles, an oscillation in which RE neurons play a leading role, as well as during interspindle lulls. They were significantly different from excitatory postsynaptic potentials and also distinct from fast prepotentials that are presumably dendritic spikes generated synaptically. Spikelets were strongly reduced by halothane, a blocker of gap junctions. Multi-site extracellular recordings performed before, during and after administration of halothane demonstrated a role for electrical coupling in the synchronization of spindling activity within the RE nucleus. Finally, computational models of RE neurons predicted that gap junctions between these neurons could mediate the spread of low-frequency activity at great distances. These experimental and modeling data suggest that electrotonic coupling within the RE nucleus plays an important role in the generation and synchronization of low-frequency (spindling) activities in the thalamus.
halothane; intracellular recordings and staining; spikelets; spindling
Mechanisms underlying seizure cessation remain elusive. The Lennox-Gastaut syndrome, a severe childhood epileptic disorder, is characterized by episodes of seizure with alternating epochs of spike-wave and fast run discharges. In a detailed computational model that incorporates extracellular potassium dynamics, we studied the dynamics of these state transitions between slow and fast oscillations. We show that dynamic modulation of synaptic transmission can cause termination of paroxysmal activity. An activity-dependent shift in the balance between synaptic excitation and inhibition towards more excitation caused seizure termination by favoring the slow oscillatory state, which permits recovery of baseline extracellular potassium concentration. We found that slow synaptic depression and change in chloride reversal potential can have similar effects on the seizure dynamics. Our results indicate a novel role for synaptic dynamics during epileptic neural activity patterns.
neocortex; synaptic plasticity; extracellular potassium concentration; intracellular chloride concentration; computational model
The subtle mechanisms of post-traumatic epileptogenesis remain unknown although the incidence of chronic epilepsy after penetrating cortical wounds is very high. Here, we investigated whether the increased frequency of seizures occurring within 6 weeks following partial deafferentation of the suprasylvian gyrus in cats is accompanied with a change in the ratio between the number of excitatory and inhibitory neurons. Immunohistochemical labeling of all neurons with neuronal-specific nuclear protein (NeuN) antibody, and of the GABAergic inhibitory neurons with either gamma-aminobutyric acid (GABA) or glutamic acid decarboxylase (GAD 65&67) antibodies, was performed on sections obtained from control and epileptic animals with chronically deafferented suprasylvian gyrus. Quantifications of labeled neurons were performed in control and at 2, 4 and 6 weeks following cortical deafferentation, in the suprasylvian and marginal gyri, both ipsi- and contra-lateral to the cortical trauma. In all epileptic animals the neuronal loss was circumscribed to the deafferented suprasylvian gyrus. Inhibitory GABAergic neurons were particularly more sensitive to cortical deafferentation than excitatory ones, leading to a progressively increasing ratio between excitation and inhibition towards excitation, which might explain the increased propensity to seizures in chronic undercut cortex.
brain injury; cortical deafferentation; epilepsy; GAD; GABA
The subtle mechanisms of post-traumatic epileptogenesis remain unknown, although the incidence of chronic epilepsy after penetrating cortical wounds is high. Here, we investigated whether the increased frequency of seizures occurring within 6 weeks following partial deafferentation of the suprasylvian gyrus in cats is accompanied with a change in the ratio between the number of excitatory and inhibitory neurons. Immuno-histochemical labeling of all neurons with neuronal-specific nuclear protein (NeuN) antibody, and of the GABAergic inhibitory neurons with either gamma-aminobutyric acid (GABA) or glutamic acid decarboxylase (GAD 65&67) antibodies, was performed on sections obtained from control and epileptic animals with chronically deafferented suprasylvian gyrus. Quantification of the labeled neurons was performed in control animals and at 2, 4, and 6 weeks following cortical deafferentation, in the suprasylvian and marginal gyri, both ipsi- and contra-lateral to the cortical trauma. In all epileptic animals, the neuronal loss was circumscribed to the deafferented suprasylvian gyrus. Inhibitory GABAergic neurons were particularly more sensitive to cortical deafferentation than excitatory ones, leading to a progressively increasing ratio between excitation and inhibition towards excitation, potentially explaining the increased propensity to seizures in chronic undercut cortex.
brain injury; cortical deafferentation; epilepsy; GABA; GAD
Slow-wave sleep is characterized by spontaneous alternations of activity and silence in corticothalamic networks, but the causes of transition from silence to activity remain unknown. We investigated local mechanisms underlying initiation of activity, using simultaneous multisite field potential, multiunit recordings, and intracellular recordings from 2 to 4 nearby neurons in naturally sleeping or anesthetized cats. We demonstrate that activity may start in any neuron or recording location, with tens of milliseconds delay in other cells and sites. Typically, however, activity originated at deep locations, then involved some superficial cells, but appeared later in the middle of the cortex. Neuronal firing was also found to begin, after the onset of active states, at depths that correspond to cortical layer V. These results support the hypothesis that switch from silence to activity is mediated by spontaneous synaptic events, whereby any neuron may become active first. Due to probabilistic nature of activity onset, the large pyramidal cells from deep cortical layers, which are equipped with the most numerous synaptic inputs and large projection fields, are best suited for switching the whole network into active state.
intracellular; intrinsic; oscillations; sleep; synaptic; synchronization
A cortically generated Lennox-Gastaut type seizure is associated with spike-wave/polyspike-wave discharges at 1.0–2.5 Hz and fast runs at 7–16 Hz. Here we studied the patterns of synchronization during runs of paroxysmal fast spikes.
Electrographic activities were recorded using multisite intracellular and field potential recordings in vivo from cats anesthetized with ketamine-xylazine. In different experiments, the recording electrodes were located either at short distances (<1 mm) or at longer distances (up to 12 mm). The main experimental findings were tested in computational models.
In the majority of cases, the onset and the offset of fast runs occurred almost simultaneously in different recording sites. The amplitude and duration of fast runs could vary by orders of magnitude. Within the fast runs, the patterns of synchronization recorded in different electrodes were as following: (i) synchronous, in phase, (ii) synchronous, with phase shift, (iii) patchy, repeated in phase/phase shift transitions and (iv) non-synchronous, slightly different frequencies in different recording sites or absence of oscillatory activity in one of the recording sites; the synchronous patterns (in phase or with phase shifts) were most common. All these patterns could be recorded in the same pair of electrodes during different seizures and they were reproduced in a computational network model. Intrinsically-bursting (IB) neurons fired more spikes per cycle than any other neurons suggesting their leading role in the fast run generation.
Once started, the fast runs are generated locally with variable correlations between neighboring cortical foci.
Synchronization; cortex; electrographic seizures; EEG; intracellular; in vivo; computational model
Epileptic seizures constitute a complex multiscale phenomenon that is characterized by synchronized hyperexcitation of neurons in neuronal networks. Recent progress in understanding pathological seizure dynamics provides crucial insights into underlying mechanisms and possible new avenues for the development of novel treatment modalities. Here we review some recent work that combines in vivo experiments and computational modeling to unravel the pathophysiology of seizures of cortical origin. We particularly focus on how activity-dependent changes in extracellular potassium concentration affects the intrinsic dynamics of neurons involved in cortical seizures characterized by spike/wave complexes and fast runs.
The influence of calcium channel distribution and geometry of the thalamocortical cell upon its tonic firing and the low threshold spike (LTS) generation was studied in a 3-compartment model, which represents soma, proximal and distal dendrites as well as in multi-compartment model using the morphology of a real reconstructed neuron. Using an uniform distribution of Ca2+ channels, we determined the minimal number of low threshold voltage-activated calcium channels and their permeability required for the onset of LTS in response to a hyperpolarizing current pulse. In the 3-compartment model, we found that the channel distribution influences the firing pattern only in the range of 3% below the threshold value of total T-channel density. In the multi-compartmental model, the LTS could be generated by only 64% of unequally distributed T-channels compared to the minimal number of equally distributed T-channels. For a given channel density and injected current, the tonic firing frequency was found to be inversely proportional to the size of the cell. However, when the Ca2+ channel density was elevated in soma or proximal dendrites, then the amplitude of LTS response and burst spike frequencies were determined by the ratio of total to threshold number of T-channels in the cell for a specific geometry.
thalamocortical cell; low-threshold spike; T-current; channel distribution