Characterization of Panglial Gap Junction Networks in the Thalamus, Neocortex, and Hippocampus Reveals a Unique Population of Glial Cells.

The thalamus plays important roles as a relay station for sensory information in the central nervous system (CNS). Although thalamic glial cells participate in this activity, little is known about their properties. In this study, we characterized the formation of coupled networks between astrocytes and oligodendrocytes in the murine ventrobasal thalamus and compared these properties with those in the hippocampus and cortex.

GABAB Receptors Regulate Extrasynaptic GABAA Receptors.

Tonic inhibitory GABA(A) receptor-mediated currents are observed in numerous cell types in the CNS, including thalamocortical neurons of the ventrobasal thalamus, dentate gyrus granule cells, and cerebellar granule cells. Here we show that in rat brain slices, activation of postsynaptic GABA(B) receptors enhances the magnitude of the tonic GABA(A) current recorded in these cell types via a pathway involving G G proteins, adenylate cyclase, and cAMP-dependent protein kinase. Using a combination of pharmacology and knockout mice, we show that this pathway is independent of potassium channels or GABA transporters.

Augmentation of Tonic GABA(A) Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABA(A) Receptors.

It is well established that impaired GABAergic inhibition within neuronal networks can lead to hypersynchronous firing patterns that are the typical cellular hallmark of convulsive epileptic seizures. However, recent findings have highlighted that a pathological enhancement of GABAergic signalling within thalamocortical circuits is a necessary and sufficient condition for nonconvulsive typical absence seizure genesis. In particular, increased activation of extrasynaptic GABA(A) receptors (eGABA(A)R) and augmented "tonic" GABA(A) inhibition in thalamocortical neurons have been demonstrated across a range of genetic and pharmacological models of absence epilepsy.

Transition to absence seizures and the role of GABA(A) receptors.

Absence seizures appear to be initiated in a putative cortical 'initiation site' by the expression of medium-amplitude 5-9Hz oscillations, which may in part be due to a decreased phasic GABA(A) receptor function. These oscillations rapidly spread to other cortical areas and to the thalamus, leading to fully developed generalized spike and wave discharges. In thalamocortical neurons of genetic models, phasic GABA(A) inhibition is either unchanged or increased, whereas tonic GABA(A) inhibition is increased both in genetic and pharmacological models.

mGluR control of interneuron output regulates feedforward tonic GABAA inhibition in the visual thalamus.

Metabotropic glutamate receptors (mGluRs) play a crucial role in regulation of phasic inhibition within the visual thalamus. Here we demonstrate that mGluR-dependent modulation of interneuron GABA release results in dynamic changes in extrasynaptic GABA(A) receptor (eGABA(A)R)-dependent tonic inhibition in thalamocortical (TC) neurons of the rat dorsal lateral geniculate nucleus (dLGN). Application of the group I selective mGluR agonist dihydroxyphenylglycine produces a concentration-dependent enhancement of both IPSC frequency and tonic GABA(A) current (I(GABA)tonic) that is due to activation of both mGluR1a and mGluR5 subtypes.

Aberrant GABA(A) receptor-mediated inhibition in cortico-thalamic networks of succinic semialdehyde dehydrogenase deficient mice.

Aberrant γ-aminobutyric acid type A (GABA(A)) receptor-mediated inhibition in cortico-thalamic networks remains an attractive mechanism for typical absence seizure genesis. Using the whole-cell patch clamp technique we examined 'phasic' and 'tonic' GABA(A) inhibition in thalamocortical neurons of somatosensory (ventrobasal, VB) thalamus, nucleus reticularis thalami (NRT) neurons, and layer 5/6 pyramidal neurons of the somatosensory (barrel) cortex of succinic semialdehyde dehydrogenase (SSADH) knock-out (SSADH(-/-)) mice that replicate human SSADH deficiency and exhibit typical absence seizures. We found increased sIPSC frequency in both VB and NRT neurons and larger sIPSC amplitude in VB neurons of SSADH(-/-) mice compared to wild-type animals, demonstrating an increase in total phasic inhibition in thalamus of SSADH(-/-) mice.

Non-neuronal, slow GABA signalling in the ventrobasal thalamus targets δ-subunit-containing GABA(A) receptors.

The rodent ventrobasal (VB) thalamus contains a relatively uniform population of thalamocortical (TC) neurons that receive glutamatergic input from the vibrissae and the somatosensory cortex, and inhibitory input from the nucleus reticularis thalami (nRT). In this study we describe γ-aminobutyric acid (GABA)(A) receptor-dependent slow outward currents (SOCs) in TC neurons that are distinct from fast inhibitory postsynaptic currents (IPSCs) and tonic currents. SOCs occurred spontaneously or could be evoked by hypo-osmotic stimulus, and were not blocked by tetrodotoxin, removal of extracellular Ca(2+) or bafilomycin A1, indicating a non-synaptic, non-vesicular GABA origin.

Enhanced tonic GABAA inhibition in typical absence epilepsy.

The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired gamma-aminobutyric acid (GABA)-ergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABA(A) receptor-dependent 'tonic' inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT-1 in the genetic models tested, and GAT-1 is crucial in governing seizure genesis.

Extrasynaptic GABAA receptors: form, pharmacology, and function.

GABA is the principal inhibitory neurotransmitter in the CNS and acts via GABA(A) and GABA(B) receptors. Recently, a novel form of GABA(A) receptor-mediated inhibition, termed "tonic" inhibition, has been described. Whereas synaptic GABA(A) receptors underlie classical "phasic" GABA(A) receptor-mediated inhibition (inhibitory postsynaptic currents), tonic GABA(A) receptor-mediated inhibition results from the activation of extrasynaptic receptors by low concentrations of ambient GABA.

Novel modes of rhythmic burst firing at cognitively-relevant frequencies in thalamocortical neurons.

It is now widely accepted that certain types of cognitive functions are intimately related to synchronized neuronal oscillations at both low (alpha/theta) (4-7/8-13 Hz) and high (beta/gamma) (18-35/30-70 Hz) frequencies. The thalamus is a key participant in many of these oscillations, yet the cellular mechanisms by which this participation occurs are poorly understood. Here we describe how, under appropriate conditions, thalamocortical (TC) neurons from different nuclei can exhibit a wide array of largely unrecognised intrinsic oscillatory activities at a range of cognitively-relevant frequencies.

NeuReal: an interactive simulation system for implementing artificial dendrites and large hybrid networks.

The dynamic clamp is a technique which allows the introduction of artificial conductances into living cells. Up to now, this technique has been mainly used to add small numbers of 'virtual' ion channels to real cells or to construct small hybrid neuronal circuits. In this paper we describe a prototype computer system, NeuReal, that extends the dynamic clamp technique to include (i) the attachment of artificial dendritic structures consisting of multiple compartments and (ii) the construction of large hybrid networks comprising several hundred biophysically realistic modelled neurons.

Thalamic T-type Ca2+ channels and NREM sleep.

T-type Ca2+ channels play a number of different and pivotal roles in almost every type of neuronal oscillation expressed by thalamic neurones during non-rapid eye movement (NREM) sleep, including those underlying sleep theta waves, the K-complex and the slow (<1 Hz) sleep rhythm, sleep spindles and delta waves. In particular, the transient opening of T channels not only gives rise to the 'classical' low threshold Ca2+ potentials, and associated high frequency burst of action potentials, that are characteristically present during sleep spindles and delta waves, but also contributes to the high threshold bursts that underlie the thalamic generation of sleep theta rhythms. The persistent opening of a small fraction of T channels, i.

Neuronal basis of the slow (<1 Hz) oscillation in neurons of the nucleus reticularis thalami in vitro.

During deep sleep and anesthesia, the EEG of humans and animals exhibits a distinctive slow (<1 Hz) rhythm. In inhibitory neurons of the nucleus reticularis thalami (NRT), this rhythm is reflected as a slow (<1 Hz) oscillation of the membrane potential comprising stereotypical, recurring "up" and "down" states. Here we show that reducing the leak current through the activation of group I metabotropic glutamate receptors (mGluRs) with either trans-ACPD [(+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid] (50-100 microM) or DHPG [(S)-3,5-dihydroxyphenylglycine] (100 microM) instates an intrinsic slow oscillation in NRT neurons in vitro that is qualitatively equivalent to that observed in vivo.

GABAA receptor-mediated tonic inhibition in thalamic neurons.

Tonic GABAA receptor-mediated inhibition is typically generated by delta subunit-containing extrasynaptic receptors. Because the delta subunit is highly expressed in the thalamus, we tested whether thalamocortical (TC) neurons of the dorsal lateral geniculate nucleus (dLGN) and ventrobasal complex exhibit tonic inhibition. Focal application of gabazine (GBZ) (50 microM) revealed the presence of a 20 pA tonic current in 75 and 63% of TC neurons from both nuclei, respectively.

The 'window' T-type calcium current in brain dynamics of different behavioural states.

All three forms of recombinant low voltage-activated T-type Ca(2)(+) channels (Ca(v)3.1, Ca(v)3.2 and Ca(v)3.

Synchronized oscillations at alpha and theta frequencies in the lateral geniculate nucleus.

In relaxed wakefulness, the EEG exhibits robust rhythms in the alpha band (8-13 Hz), which decelerate to theta (approximately 2-7 Hz) frequencies during early sleep. In animal models, these rhythms occur coherently with synchronized activity in the thalamus. However, the mechanisms of this thalamic activity are unknown.

Novel neuronal and astrocytic mechanisms in thalamocortical loop dynamics.

In this review, we summarize three sets of findings that have recently been observed in thalamic astrocytes and neurons, and discuss their significance for thalamocortical loop dynamics. (i) A physiologically relevant 'window' component of the low-voltage-activated, T-type Ca(2+) current (I(Twindow)) plays an essential part in the slow (less than 1 Hz) sleep oscillation in adult thalamocortical (TC) neurons, indicating that the expression of this fundamental sleep rhythm in these neurons is not a simple reflection of cortical network activity. It is also likely that I(Twindow) underlies one of the cellular mechanisms enabling TC neurons to produce burst firing in response to novel sensory stimuli.

Cellular mechanisms of the slow (<1 Hz) oscillation in thalamocortical neurons in vitro.

The slow (<1 Hz) rhythm is a defining feature of the electroencephalogram during sleep. Since cortical circuits can generate this rhythm in isolation, it is assumed that the accompanying slow oscillation in thalamocortical (TC) neurons is largely a passive reflection of neocortical activity. Here we show, however, that by activating the metabotropic glutamate receptor (mGluR), mGluR1a, cortical inputs can recruit intricate cellular mechanisms that enable the generation of an intrinsic slow oscillation in TC neurons in vitro with identical properties to those observed in vivo.