Thalamic Reticular Neurons Research Articles

Differential Distribution of Three Members of a Gene Family Encoding Low Voltage-Activated (T-Type) Calcium Channels

Low voltage-activated (T-type) calcium currents are observed in many central and peripheral neurons and display distinct physiological and functional properties. Using in situ hybridization, we have localized central and peripheral nervous system expression of three transcripts (alpha1G, alpha1H, and alpha1I) of the T-type calcium channel family (CaVT). Each mRNA demonstrated a unique distribution, and expression of the three genes was largely complementary. We found high levels of expression of these transcripts in regions associated with prominent T-type currents, including inferior olivary and thalamic relay neurons (which expressed alpha1G), sensory ganglia, pituitary, and dentate gyrus granule neurons (alpha1H), and thalamic reticular neurons (alpha1I and alpha1H). Other regions of high expression included the Purkinje cell layer of the cerebellum, the bed nucleus of the stria terminalis, the claustrum (alpha1G), the olfactory tubercles (alpha1H and alpha1I), and the subthalamic nucleus (alpha1I and alpha1G). Some neurons expressed high levels of all three genes, including hippocampal pyramidal neurons and olfactory granule cells. Many brain regions showed a predominance of labeling for alpha1G, including the amygdala, cerebral cortex, rostral hypothalamus, brainstem, and spinal cord. Exceptions included the basal ganglia, which showed more prominent labeling for alpha1H and alpha1I, and the olfactory bulb, the hippocampus, and the caudal hypothalamus, which showed more even levels of all three transcripts. Our results are consistent with the hypothesis that differential gene expression underlies pharmacological and physiological heterogeneity observed in neuronal T-type calcium currents, and they provide a molecular basis for the study of T-type channels in particular neurons.

Self-sustained rhythmic activity in the thalamic reticular nucleus mediated by depolarizing GABAA receptor potentials.

Intracellular recordings from reticular thalamic (RE) neurons in vivo revealed inhibitory postsynaptic potentials (IPSPs) between RE cells that reversed and became depolarizing at the hyperpolarized membrane potentials that occur during sleep. These excitatory IPSPs can directly trigger low-threshold spikes (LTSs). The oscillatory mechanisms underlying IPSP-triggered LTSs crowned by spike bursts were investigated in models of isolated RE networks. In a one-dimensional network model, external stimulation evoked waves of excitation propagating at a constant velocity of 25-150 cells per second. In a large-scale, two-dimensional model of the reticular nucleus, the network showed transient or self-sustained oscillations controlled by the maximum conductance of the low-threshold calcium current and the membrane potential. This model predicts that the isolated reticular nucleus could initiate sequences of spindle oscillations in thalamocortical networks in vivo.

Leading role of thalamic over cortical neurons during postinhibitory rebound excitation.

The postinhibitory rebound excitation is an intrinsic property of thalamic and cortical neurons that is implicated in a variety of normal and abnormal operations of neuronal networks, such as slow or fast brain rhythms during different states of vigilance as well as seizures. We used dual simultaneous intracellular recordings of thalamocortical neurons from the ventrolateral nucleus and neurons from the motor cortex, together with thalamic and cortical field potentials, to investigate the temporal relations between thalamic and cortical events during the rebound excitation that follows prolonged periods of stimulus-induced inhibition. Invariably, the rebound spike-bursts in thalamocortical cells occurred before the rebound depolarization in cortical neurons and preceded the peak of the depth-negative, rebound field potential in cortical areas. Also, the inhibitory-rebound sequences were more pronounced and prolonged in cortical neurons when elicited by thalamic stimuli, compared with cortical stimuli. The role of thalamocortical loops in the rebound excitation of cortical neurons was shown further by the absence of rebound activity in isolated cortical slabs. However, whereas thalamocortical neurons remained hyperpolarized after rebound excitation, because of the prolonged spike-bursts in inhibitory thalamic reticular neurons, the rebound depolarization in cortical neurons was prolonged, suggesting the role of intracortical excitatory circuits in this sustained activity. The role of intrathalamic events in triggering rebound cortical activity should be taken into consideration when analyzing information processes at the cortical level; at each step, corticothalamic volleys can set into action thalamic inhibitory neurons, leading to rebound spike-bursts that are transferred back to the cortex, thus modifying cortical activities.

Computer simulations of stimulus dependent state switching in basic circuits of bursting neurons

We investigate the ability of oscillating neural circuits to switch between different states of oscillation in two basic neural circuits. We model two quite distinct small neural circuits. The first circuit is based on invertebrate central pattern generator (CPG) studies [A. I. Selverston and M. Moulins, The Crustacean Stomatogastric System (Springer-Verlag, Berlin, 1987)] and is composed of two neurons coupled via both gap junction and inhibitory synapses. The second consists of coupled pairs of interconnected thalamocortical relay and thalamic reticular neurons with both inhibitory and excitatory synaptic coupling. The latter is an elementary unit of the thalamic networks passing sensory information to the cerebral cortex [M. Steriade, D. A. McCormick, and T. J. Sejnowski, Science 262, 679 (1993)]. Both circuits have contradictory coupling between symmetric parts. The thalamocortical model has excitatory and inhibitory connections and the CPG has reciprocal inhibitory and electrical coupling. We describe the dynamics of the individual neurons in these circuits by conductance based ordinary differential equations of Hodgkin-Huxley type [J. Physiol. (London) 117, 500 (1952)]. Both model circuits exhibit bistability and hysteresis in a wide region of coupling strengths. The two main modes of behavior are in-phase and out-of-phase oscillations of the symmetric parts of the network. We investigate the response of these circuits, while they are operating in bistable regimes, to externally imposed excitatory spike trains with varying interspike timing and small amplitude pulses. These are meant to represent spike trains received by the basic circuits from sensory neurons. Circuits operating in a bistable region are sensitive to the frequency of these excitatory inputs. Frequency variations lead to changes from in-phase to out-of-phase coordination or vice versa. The signaling information contained in a spike train driving the network can place the circuit into one or another state depending on the interspike interval and this happens within a few spikes. These states are maintained by the basic circuit after the input signal is ended. When a new signal of the correct frequency enters the circuit, it can be switched to another state with the same ease.

Spike-wave complexes and fast components of cortically generated seizures. IV. Paroxysmal fast runs in cortical and thalamic neurons.

In the preceding papers of this series, we have analyzed the cellular patterns and synchronization of neocortical seizures occurring spontaneously or induced by electrical stimulation or cortical infusion of bicuculline under a variety of experimental conditions, including natural states of vigilance in behaving animals and acute preparations under different anesthetics. The seizures consisted of two distinct components: spike-wave (SW) or polyspike-wave (PSW) at 2-3 Hz and fast runs at 10-15 Hz. Because the thalamus is an input source and target of cortical neurons, we investigated here the seizure behavior of thalamic reticular (RE) and thalamocortical (TC) neurons, two major cellular classes that have often been implicated in the generation of paroxysmal episodes. We performed single and dual simultaneous intracellular recordings, in conjunction with multisite field potential and extracellular unit recordings, from neocortical areas and RE and/or dorsal thalamic nuclei under ketamine-xylazine and barbiturate anesthesia. Both components of seizures were analyzed, but emphasis was placed on the fast runs because of their recent investigation at the cellular level. 1) The fast runs occurred at slightly different frequencies and, therefore, were asynchronous in various cortical neuronal pools. Consequently, dorsal thalamic nuclei, although receiving convergent inputs from different neocortical areas involved in seizure, did not express strongly synchronized fast runs. 2) Both RE and TC cells were hyperpolarized during seizure episodes with SW/PSW complexes and relatively depolarized during the fast runs. As known, hyperpolarization of thalamic neurons deinactivates a low-threshold conductance that generates high-frequency spike bursts. Accordingly, RE neurons discharged prolonged high-frequency spike bursts in close time relation with the spiky component of cortical SW/PSW complexes, whereas they fired single action potentials, spike doublets, or triplets during the fast runs. In TC cells, the cortical fast runs were reflected as excitatory postsynaptic potentials appearing after short latencies that were compatible with monosynaptic activation through corticothalamic pathways. 3) The above data suggested the cortical origin of these seizures. To further test this hypothesis, we performed experiments on completely isolated cortical slabs from suprasylvian areas 5 or 7 and demonstrated that electrical stimulation within the slab induces seizures with fast runs and SW/PSW complexes, virtually identical to those elicited in intact-brain animals. The conclusion of all papers in this series is that complex seizure patterns, resembling those described at the electroencephalogram level in different forms of clinical seizures with SW/PSW complexes and, particularly, in the Lennox-Gastaut syndrome of humans, are generated in neocortex. Thalamic neurons reflect cortical events as a function of membrane potential in RE/TC cells and degree of synchronization in cortical neuronal networks.

Computational Models of Thalamocortical Augmenting Responses

Repetitive stimulation of the dorsal thalamus at 7-14 Hz produces an increasing number of spikes at an increasing frequency in neocortical neurons during the first few stimuli. Possible mechanisms underlying these cortical augmenting responses were analyzed with a computer model that included populations of thalamocortical cells, thalamic reticular neurons, up to two layers of cortical pyramidal cells, and cortical inhibitory interneurons. Repetitive thalamic stimulation produced a low-threshold intrathalamic augmentation in the model based on the deinactivation of the low-threshold Ca2+ current in thalamocortical cells, which in turn induced cortical augmenting responses. In the cortical model, augmenting responses were more powerful in the "input" layer compared with those in the "output" layer. Cortical stimulation of the network model produced augmenting responses in cortical neurons in distant cortical areas through corticothalamocortical loops and low-threshold intrathalamic augmentation. Thalamic stimulation was more effective in eliciting augmenting responses than cortical stimulation. Intracortical inhibition had an important influence on the genesis of augmenting responses in cortical neurons: A shift in the balance between intracortical excitation and inhibition toward excitation transformed an augmenting responses to long-lasting paroxysmal discharge. The predictions of the model were compared with in vivo recordings from neurons in cortical area 4 and thalamic ventrolateral nucleus of anesthetized cats. The known intrinsic properties of thalamic cells and thalamocortical interconnections can account for the basic properties of cortical augmenting responses.

Anatomical and physiological considerations in thalamic rhythm generation.

The thalamus, known as the pacemaker for spindle rhythms in sleep, has several enabling features that promote such pacemaking. These include a circuitry that interconnects large groups of excitatory and inhibitory neurons, all of which are essentially capable of firing high-frequency 'bursts' of discharges. Bursts in thalamic reticular neurons produce powerful inhibition in thalamic relay neurons, which leads to rebound excitation. The timing properties of the inhibition regulate the network activity by controlling rebound burst latency. Anatomical features within thalamus such as convergence and divergence determine the spread and synchronization of pacemaking activity. The anatomical basis of divergence, i.e. the degree of axonal arborization of elements within the thalamic circuit, can be functionally modified in a dynamic fashion by biochemical pathways that regulate the properties of synaptic release. These data suggest that it will be possible to therapeutically regulate the thalamus to modify not only the propensity to sleep but also forms of epilepsy that rely on similar thalamic circuitry.

Localization of CCK receptors in thalamic reticular neurons: a modeling study.

In an earlier experimental study, intracellular recording suggested that cholecystokinin (CCK) suppresses a K+ conductance in thalamic reticular (RE) neurons, yet the reversal potential of the CCK response, revealed using voltage clamp, was hyperpolarized significantly relative to the K+ equilibrium potential. Here, biophysical models of RE neurons were developed and used to test whether suppression of the K+ conductance, gK, can account for the CCK response observed in vitro and also to determine the likely site of CCK receptors on RE neurons. Suppression of gK in model RE neurons can reproduce the relatively hyperpolarized reversal potential of CCK responses found using voltage clamp if the voltage clamp becomes less effective at hyperpolarized potentials. Three factors would reduce voltage-clamp effectiveness in this model: the nonnegligible series resistance of the voltage-clamp electrode, a hyperpolarization-activated mixed cation current (Ih) in RE neurons, and the dendritic location of CCK-sensitive K+ channels. Although suppression of gK in the dendritic compartments of model RE neurons simulates both the magnitude and reversal potential of the CCK response, suppression of gK in just the somatic compartment of model RE neurons fails to do so. Thus the model predicts that CCK should effectively suppress K+ conductance RE neuron dendrites and thereby regulate burst firing in RE neurons. This may explain the potent effects of CCK on intrathalamic oscillations in vitro.

The Globus Pallidus Sends Axons to the Thalamic Reticular Nucleus Neurons Projecting to the Centromedian Nucleus of the Thalamus: A Light and Electron Microscope Study in the Cat

We examined whether light and electron microscopically projection fibers from the globus pallidus (GP) of the cat might terminate on neurons of the thalamic reticular nucleus (RT) sending axons to the centromedian thalamic nucleus (CM). In the first group of experiments, wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) was injected into the GP, and anterogradely labeled preterminal and terminal-like elements were seen in the anterior part of RT. At the anterior pole of RT, these labeled elements were localized in its lateral portion. In the second group of experiments, the retrograde labeling method with WGA-HRP was combined with the degeneration method using kainic acid. In each cat, lesion was placed stereotaxically in the GP by kainic acid injection, and WGA-HRP was then injected into the CM ipsilateral to the kainic acid injection. In the rostral part of RT, a considerable number of degenerated axon terminals deriving from GP were seen to establish synaptic contact with dendritic and somatic profiles, which were retrogradely labeled by WGA-HRP injections in CM. The results indicate that GP innervates directly RT nucleus neurons projecting to CM.

Calretinin Immunoreactivity in the Developing Thalamus of the Rat: A Maker of Early Generated Thalamic Cells

The present work was aimed to study the immunocytochemical localization of the calcium-binding protein, calretinin, in the rat thalamus from embryonic day 14 to the third postnatal week. In the adult rat thalamus, calretinin immunoreactivity is intensely expressed in some intralaminar and midline nuclei, as well as in selected regions of the reticular nucleus. At embryonic day 14, calretinin was expressed by immature and migrating neurons and fibres laterally to the neuroepithelium of the diencephalic vesicle in the region identified as reticular neuroepithelium. At embryonic day 16, immunoreactive neurons were present in the primordium of the reticular nucleus and in the region of the reticular thalamic migration, where neurons showed the morphology of migratory cells. At the end of embryonic development and in the first postnatal week, calretinin-positive neurons were observed in selected region of the reticular nucleus and it was intensely expressed in some intralaminar and midline nuclei. Bands of immunopositive fibres were also observed crossing the thalamus. During the second postnatal week, the immunolabelling in the reuniens, rhomboid, paraventricular and central medial thalamic nuclei remains very intense while a decrease of immunoreactivity in mediodorsal, centrolateral and laterodorsal nuclei was observed. The immunostaining of fibres, particularly evident in the perinatal period, progressively decreased and it was no longer visible by the end of the second postnatal week when the distribution and intensity of calretinin immunostaining was similar to that observed in the adult rat thalamus. The present findings indicate that the immunolocalization of calretinin can be used to identify subsets of thalamic neuronal population during pre- and postnatal maturation allowing also the detection of the migratory pattern of early generated reticular thalamic neurons.

GABAA receptor-mediated Cl- currents in rat thalamic reticular and relay neurons.

GABAA receptor-mediated Cl- currents in rat thalamic reticular and relay neurons. J. Neurophysiol. 78: 2280-2286, 1997. Spontaneous and evoked inhibitory postsynaptic currents (sIPSCs and eIPSCs) and responses to exogenously applied gamma-aminobutyric acid (GABA), mediated by GABA type A (GABAA) receptors, were recorded in inhibitory neurons of nucleus reticularis thalami (nRt) and their target relay cells in ventrobasal (VB) nuclei by using patch clamp techniques in rat thalamic slices. The decay of sIPSCs in both nRt and VB neurons was best fitted with two exponential components. The decay time constants of sIPSCs in nRt neurons were much slower (tau1 = 38 ms; tau2 = 186 ms) than those previously reported in a variety of preparations and two to three times slower than those in VB neurons (tau1 = 17 ms; tau2 = 39 ms). GABAA receptor-mediated Cl- currents directly evoked by local GABA application also had a much slower decay time constant in nRt (225 ms) than in VB neurons (115 ms). Slow decay of GABA responses enhances the efficacy of recurrent intranuclear inhibition in nRt. The results suggest a functional diversity of GABAA receptors that may relate to the known heterogeneity of GABAA receptor subunits in these two thalamic nuclei.

Short-Term Plasticity during Intrathalamic Augmenting Responses in Decorticated Cats

The intrathalamic mechanisms of frequency-dependent augmenting responses were investigated in decorticated cats by means of intracellular recordings from thalamocortical (TC) neurons in ventrolateral (VL) nucleus, including simultaneous impalements from two TC neurons. Pulse trains (10 Hz) applied to VL nucleus elicited two types of augmenting responses: (1) in 68% of cells, the incremental responses occurred on a progressive depolarization associated with the decrease in IPSPs produced by preceding stimuli in the train; (2) in the remaining cells, progressively growing low-threshold (LT) responses resulted from the enhancement of Cl--dependent IPSPs, giving rise to postinhibitory rebound bursts, followed by a self-sustained sequence of spindle waves. Although in some TC cells the augmenting responses developed from LT responses once the latter reached a given level of depolarization, other neurons displayed augmenting responses immediately after the early antidromic spike that depolarized the neuron to the required level, without an intermediate step of LT rebound. Repeated pulse trains led to a progressive and persistent increase in slow depolarizing responses of TC cells, as well as to a persistent and prolonged decrease in the amplitudes of the IPSPs. On the basis of parallel experiments, we propose that the two types of augmentation in TC cells are a result of contrasting responses of thalamic reticular neurons evoked by repetitive thalamic stimuli: decremental responses, which may account for disinhibition leading to depolarizing responses in TC cells, and incremental responses, explaining the progressive hyperpolarization of TC cells. These data demonstrate that frequency-dependent changes in neuronal excitability are present in the thalamus of a decorticated hemisphere and suggest that short-term plasticity processes in the gateway to the cerebral cortex may decisively influence cortical excitability during repetitive responses.

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.

Sleep and arousal: thalamocortical mechanisms.

Thalamocortical activity exhibits two distinct states: (a) synchronized rhythmic activity in the form of delta, spindle, and other slow waves during EEG-synchronized sleep and (b) tonic activity during waking and rapid-eye-movement sleep. Spindle waves are generated largely through a cyclical interaction between thalamocortical and thalamic reticular neurons involving both the intrinsic membrane properties of these cells and their anatomical interconnections. Specific alterations in the interactions between these cells can result in the generation of paroxysmal events resembling absence seizures in children. The release of several different neurotransmitters from the brain stem, hypothalamus, basal forebrain, and cerebral cortex results in a depolarization of thalamocortical and thalamic reticular neurons and an enhanced excitability in many cortical pyramidal cells, thereby suppressing the generation of sleep rhythms and promoting a state that is conducive to sensory processing and cognition.

State-dependent fluctuations of low-frequency rhythms in corticothalamic networks

We have studied the variations in the degree of correlated firing within the low-frequency sleep rhythms (<15 Hz) between cortical, thalamic reticular and thalamocortical neurons during changes in the amplitude and frequency of brain electrical activity in anaesthetized cats. Extracellular discharges of neuronal groups of two to five physiologically identified cortical and thalamic units were recorded simultaneously with independent microelectrodes. The firing patterns and the temporal correlation between spike-trains were evaluated by auto- and crosscorrelograms. Although the animals were under deep anaesthesia, additional doses of the same or different anaesthetics were able to alter the electroencephalographic pattern, inducing waves with higher amplitude. Similar transitions occurred spontaneously. We found that the presence of rhythmic behaviour in cells of corticothalamic networks, as well as their degree of correlated firing, was extremely sensitive to even slight alterations in the state of the electroencephalogram. Cells belonging to the same functional system, but located distantly, became highly synchronized upon the increased amplitude of brain waves. Thus, an electroencephalogram characterized by slow waves corresponds to a state of rhythmic and correlated firing among cortical and thalamic neurons. The highly coherent activity during sleep patterns transcends the borders which limit the functioning during the waking brain.

Synchronization of low-frequency rhythms in corticothalamic networks

We have investigated the degree of synchronization between cortical, thalamic reticular and thalamocortical neurons of cats during low-frequency (<15 Hz) sleep-like oscillations, as they appear under anaesthesia. We have also studied the effects exerted by cortical stimulation on the synchronization among thalamic units. Parallel experiments [Steriade et al. (1996) J. Neurosci. 16, 392–417] in this laboratory have demonstrated the similarity between the slow oscillation (<1 Hz) under ketamine-xylazine anaesthesia and that occurring during the natural state of resting sleep. Spontaneous activity was recorded simultaneously, with independent microelectrodes, from groups of two to five physiologically identified neurons. The rhythmicity of spontaneous activity and the temporal relations between cellular discharges were statistically evaluated by auto- and crosscorrelation techniques. We have found no topography in the distribution of synchronization between thalamic reticular and thalamocortical cells. Only the slow, cortical-generated oscillation (<1 Hz) displayed a stable frequency and correlation among groups of cortical and thalamic cells. The other two sleep oscillations (thalamic-generated spindles at 7–14 Hz and clock-like delta at 1–4 Hz) fluctuated in frequency and the degree of correlation between neurons varied. Cortical volleys entrained and synchronized thalamic cells, and triggered synchronized spindling in the thalamus. These results extend for large populations of cortical and thalamic neurons the phase relations found in intracellular recordings. [Contreras and Steriade (1995) J. Neurosci. 15, 604–622; Steriade and Contreras (1995) J. Neurosci. 15, 623–642]

Interaction between low voltage-activated currents in reticular thalamic neurons in a rat model of absence epilepsy.

A transient potassium (K+) outward current (IA) contributes to the distinctive patterns of low-threshold spike firing observed in various classes of thalamic neurons through a functional interaction with a calcium (Ca2+)-mediated inward current (IT). The present study was undertaken to investigate the properties of transient K+ currents and their interaction with IT in neurons of the reticular thalamic nucleus, and to compare these properties in reticular thalamic nucleus neurons from a rat model of absence epilepsy, designated the Genetic Absence Epilepsy Rat from Strasbourg (GAERS), with those from a Non-epileptic Control strain (NEC). This comparative approach appeared to be particularly important in view of the recent finding of a selective increase in IT in reticular thalamic nucleus neurons from GAERS. Neurons were acutely isolated from the reticular thalamic nucleus through enzymatic procedures, and identified by morphological and immunocytochemical criteria. Ionic currents were analysed using whole-cell patch-clamp techniques. Transient K+ currents in reticular thalamic nucleus neurons with properties indicative of IA activated at approximately -55 mV (with half-activation at -27 and -33 mV in NEC and GAERS respectively), declined rapidly with a voltage-dependent time constant (tau = 4 ms at +45 mV), were 50% steady-state-inactivated at -81 and -86 mV in the two strains of rats respectively, and rapidly recovered from inactivation with a monoexponential time course (tau = 31 and 37 ms respectively). No significant differences in IA properties or densities were found between reticular thalamic nucleus neurons from GAERS and NEC rats. Analysis of the interaction between IA and IT indicated a shift in the balance between the two opposing membrane conductances towards the generation of a low-voltage-activated inward current in reticular thalamic nucleus neurons from GAERS compared with NEC, and a lack of IA to functionally compensate for this shift, which in turn may contribute to pathological forms of low-threshold spike firing characterizing spike-and-wave discharges.

GABAA receptor function in developing rat thalamic reticular neurons: whole cell recordings of GABA-mediated currents and modulation by clonazepam.

1. Nucleus reticularis thalami (NRT) is a nucleus composed entirely of GABAergic neurons, which functions as a pacemaker to synchronize thalamocortical oscillations. To study the functional properties of GABAergic inhibition mediated through activation of gamma-aminobuturic acid-A (GABAA) receptors in these cells, neurons were isolated acutely from NRT at various postnatal developmental stages and recorded from using whole cell patch-clamp techniques. 2. Application of GABA to NRT neurons elicited a large, bicuculline sensitive current with an average reversal potential of -60.6 +/- 1.9 mV (mean +/- SD) in postnatal day (p) 19-21 neurons and -51.2 +/- 3.1 mV in p7 neurons, presumably mediated through activation of a GABAA-mediated chloride conductance. The potency of GABA in activating GABAA receptors decreased significantly with postnatal development in NRT neurons and was best fitted with EC50s of 24.9, 33.9, and 67.2 microM, in neurons isolated from p5-9, p18-25, and p58-74 rats, respectively. The density of GABAA receptors in the membranes of NRT neurons increased significantly with postnatal development. In addition, the GABA current decay rate slowed significantly in neurons isolated from older animals relative to early postnatal rat pups. 3. Both the potency and efficacy of benzodiazepine augmentation of GABAA responses in NRT neurons increased significantly with development. The EC50 of clonazepam decreased from 26 to 6 nM in p5-9 and p58-74 NRT neurons, respectively, whereas the efficacy increased from 126 to 163% augmentation over the same developmental range. 4. The elevated efficacy of clonazepam (CNZ) in NRT neurons relative to thalamic and cortical neurons, particularly in neurons isolated from adult (> p58) rats, is consistent with the anticonvulsant profile of this drug in controlling Generalized Absence epilepsy. Augmenting inhibition within NRT would enhance NRT/ NRT inhibitory connections and thereby decrease the amplitude of NRT-mediated synchronizing inhibitory postsynaptic potentials onto thalamus (where CNZ has low efficacy), in turn making it more difficult to elicit burst firing in thalamus due to deinactivation and subsequent activation of the low-threshold Ca2+ current. 5. The present developmental profile of GABAA responses in GABAergic NRT neurons provides data important in understanding the role of GABAergic inhibition within NRT in the modulation of normal and pathological thalamocortical rhythms in the brain and is also relevant in understanding potential differences in GABAA receptor physiology and pharmacology in GABAergic interneurons relative to glutamatergic neurons.

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.

Dendritic arbors of neurons from different regions of the rat thalamic reticular nucleus share a similar orientation

Neurons in different regions of the rat thalamic reticular nucleus were labeled with biotin dextran amine and reconstructed. When viewed in coronal section, some neurons had a radial dendritic tree while others had dorso-ventrally elongated arbors. When rotated, all the neurons had a planar, disc-shaped dendritic field with the dendrites orientated parallel to the long axis of the nucleus. We conclude that all thalamic reticular nucleus neurons have a similar dendritic morphology and orientation.