Astrocytes respond to chemical, electrical and mechanical stimuli with transient increases in intracellular calcium concentration ([Ca2+]i). We now show that astrocytes in situ display intrinsic [Ca2+]i oscillations that are not driven by neuronal activity. These spontaneous astrocytic oscillations can propagate as waves to neighboring astrocytes and trigger slowly decaying NMDA receptor-mediated inward currents in neurons located along the wave path. These findings show that astrocytes in situ can act as a primary source for generating neuronal activity in the mammalian central nervous system.

The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired GABAergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA 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 critical in governing seizure genesis. Extrasynaptic GABAA receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABAA receptors is sufficient to elicit both electrographic and behavioural correlates of seizures in normal animals. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic significance, and highlight novel therapeutic targets for the treatment of absence epilepsy.

Childhood absence epilepsy is an idiopathic, generalized non-convulsive epilepsy with a multifactorial genetic aetiology. Molecular-genetic analyses of affected human families and experimental models, together with neurobiological investigations, have led to important breakthroughs in the identification of candidate genes and loci, and potential pathophysiological mechanisms for this type of epilepsy. Here, we review these results, and compare the human and experimental phenotypes that have been investigated. Continuing efforts and comparisons of this type will help us to elucidate the multigenetic traits and pathophysiology of this form of generalized epilepsy.

During relaxed wakefulness, the human brain exhibits pronounced rhythmic electrical activity in the alpha frequency band (8-13 Hz). This activity consists of 3 main components: the classic occipital alpha rhythm, the Rolandic mu rhythm, and the so-called third rhythm. In recent years, the long-held belief that alpha rhythms are strongly influenced by the thalamus has been confirmed in several animal models and, in humans, is well supported by numerous noninvasive imaging studies. Of specific importance is the emergence of 2 key cellular thalamic mechanisms, which come together to generate locally synchronized alpha activity. First, a novel form of rhythmic burst firing, termed high-threshold (HT) bursting, which occurs in a specialized subset of thalamocortical (TC) neurons, and second, the interconnection of this subset via gap junctions (GJs). Because repetitive HT bursting in TC neurons occurs in the range of 2 to 13 Hz, with the precise frequency increasing with increasing depolarization, the same cellular components that underlie thalamic alpha rhythms can also lead to theta (2-7 Hz) rhythms when the TC neuron population is less depolarized. As such, this scenario can explain both the deceleration of alpha rhythms that takes place during early sleep and the chronic slowing that characterizes a host of neurological and psychiatric disorders.

The slow (<1 Hz) rhythm, the most significant EEG signature of non-rapid eye movement (NREM) sleep, is generally viewed as originating exclusively from neocortical networks. Here we argue that the full manifestation of this fundamental sleep oscillation within a corticothalamic module requires the dynamic interaction of three cardinal oscillators: a predominantly synaptically-based cortical oscillator and two intrinsic, conditional thalamic oscillators. The functional implications of this hypothesis are discussed in relation to other key EEG features of NREM sleep, with respect to coordinating activities in local and distant neuronal assemblies and in the context of facilitating cellular and network plasticity during slow wave sleep.Although membrane potential fluctuations at a low frequency had already been observed in neurons of the rat cortex in vivo 1 , the discovery of the slow (<1 Hz) rhythm in the EEG, and of its cellular counterpart, the slow (<1 Hz) oscillation, rests with the pioneering work of Mircea Steriade and his coworkers 2 -4 . In 1993, using intracellular microelectrode recordings from morphologically identified neurons in different layers of the sensory, motor and association cortex of anesthetized cats (Fig. 1a), these authors described the presence of a slow oscillation of the membrane potential, consisting of regularly repeating sequences of depolarizations (most often with firing) and hyperpolarizations (with no firing) at a low (0.2 -0.9 Hz) frequency 2 , 3 , which are nowadays commonly referred to as UP and DOWN states, respectively (Figs. 1b and 2a) (Supplementary Note A). The slow oscillation was also present in the glutamatergic thalamocortical (TC) neurons of various thalamic nuclei and in the GABAergic neurons of the nucleus reticularis thalami (NRT), with the respective UP and DOWN states showing good temporal correlation with the corresponding cortical states and with the respective negative and positive depth-EEG waves 4 (Figs. 1b and 2b,c). Other key findings from that original series of studies were that the slow oscillation could group together periods of sleep spindles and delta waves during its UP and DOWN states 2 , 3 , respectively, and that it was present in a cerveau isolé preparation 3 . Moreover, the slow oscillation in cortex was shown to survive electrolytic lesions of extensive thalamic territories or destruction of TC neurons by kainic acid 3 , leading to the conclusion that this rhythm is generated in the neocortex and then imposed on recipient thalamic territories 4 .In the intervening 16 years, extensive and ground-breaking investigations of the slow (<1 Hz) rhythm/oscillation, both in humans and in experimental animals, have now have provided us with a remarkably detailed picture of the salient features of this brain activity 5 -14 , powerful insights into its intricate mechanisms 15 -25 and a clear window into its potential physiological significance 26 -33 . However, despite the presence of compelling evidence to the contrary 4 , 15 , 18 , 20 , 34 -...