From a structural perspective, the predominant glial cell of the central nervous system, the astrocyte, is positioned to regulate synaptic transmission and neurovascular coupling: the processes of one astrocyte contact tens of thousands of synapses, while other processes of the same cell form endfeet on capillaries and arterioles. The application of subcellular imaging of Ca²⁺ signaling to astrocytes now provides functional data to support this structural notion. Astrocytes express receptors for many neurotransmitters, and their activation leads to oscillations in internal Ca²⁺. These oscillations induce the accumulation of arachidonic acid and the release of the chemical transmitters glutamate, d-serine, and ATP. Ca²⁺ oscillations in astrocytic endfeet can control cerebral microcirculation through the arachidonic acid metabolites prostaglandin E₂ and epoxyeicosatrienoic acids that induce arteriole dilation, and 20-HETE that induces arteriole constriction. In addition to actions on the vasculature, the release of chemical transmitters from astrocytes regulates neuronal function. Astrocyte-derived glutamate, which preferentially acts on extrasynaptic receptors, can promote neuronal synchrony, enhance neuronal excitability, and modulate synaptic transmission. Astrocyte-derived d-serine, by acting on the glycine-binding site of the N-methyl-d-aspartate receptor, can modulate synaptic plasticity. Astrocyte-derived ATP, which is hydrolyzed to adenosine in the extracellular space, has inhibitory actions and mediates synaptic cross-talk underlying heterosynaptic depression. Now that we appreciate this range of actions of astrocytic signaling, some of the immediate challenges are to determine how the astrocyte regulates neuronal integration and how both excitatory (glutamate) and inhibitory signals (adenosine) provided by the same glial cell act in concert to regulate neuronal function.

Seizures in focal epilepsies are sustained by a highly synchronous neuronal discharge that arises at restricted brain sites and subsequently spreads to large portions of the brain. Despite intense experimental research in this field, the earlier cellular events that initiate and sustain a focal seizure are still not well defined. Their identification is central to understand the pathophysiology of focal epilepsies and to develop new pharmacological therapies for drug-resistant forms of epilepsy. The prominent involvement of astrocytes in ictogenesis was recently proposed. We test here whether a cooperation between astrocytes and neurons is a prerequisite to support ictal (seizure-like) and interictal epileptiform events. Simultaneous patch-clamp recording and Ca²⁺ imaging techniques were performed in a new in vitro model of focal seizures induced by local applications of N-methyl-D-aspartic acid (NMDA) in rat entorhinal cortex slices. We found that a Ca²⁺ elevation in astrocytes correlates with both the initial development and the maintenance of a focal, seizure-like discharge. A delayed astrocyte activation during ictal discharges was also observed in other models (including the whole in vitro isolated guinea pig brain) in which the site of generation of seizure activity cannot be precisely monitored. In contrast, interictal discharges were not associated with Ca²⁺ changes in astrocytes. Selective inhibition or stimulation of astrocyte Ca²⁺ signalling blocked or enhanced, respectively, ictal discharges, but did not affect interictal discharge generation. Our data reveal that neurons engage astrocytes in a recurrent excitatory loop (possibly involving gliotransmission) that promotes seizure ignition and sustains the ictal discharge. This neuron–astrocyte interaction may represent a novel target to develop effective therapeutic strategies to control seizures. In focal epilepsy, seizures are generated by a localized, synchronous neuronal electrical discharge that may spread to large portions of the brain. Despite intense experimental research in this field, a key question relevant to the human epilepsy condition remains completely unanswered: what are the cellular events that lead to the onset of a seizure in the first place? In various in vitro models of seizures using rodent brain slices, we simultaneously recorded neuronal firing and Ca²⁺ signals both from neurons and from astrocytes, the principal population of glial cells in the brain. We found that activation of astrocytes by neuronal activity and signalling from astrocytes back to neurons contribute to the initiation of a focal seizure. This reciprocal excitatory loop between neurons and astrocytes represents a new mechanism in the pathophysiology of epilepsy that should be considered by those aiming to develop more effective therapies for epilepsies that are not controlled by currently available treatments.

Key points: In focal epilepsy the propagation of seizure discharges arising at restricted brain sites is opposed by feedforward inhibition. Failure of this inhibition marks focal seizure propagation to distant neurons. The cellular source of inhibition and the mechanism of inhibition failure are, however, undefined. Here we reveal that a subclass of GABAergic interneurons, i.e. the parvalbumin‐expressing, fast‐spiking interneurons, are a main source of the inhibitory signal that locally restrains seizures. Furthermore, a firing impairment in these interneurons, probably due to a drastic membrane depolarization, is an important event that by reducing the overall strength of local inhibition allows seizures to propagate across the cortex. Our data suggest that modulation of fast‐spiking interneuron activity may represent a new therapeutic strategy to prevent generalization of focal epilepsies. Abstract  In different animal models of focal epilepsy, seizure‐like ictal discharge propagation is transiently opposed by feedforward inhibition. The specific cellular source of this signal and the mechanism by which inhibition ultimately becomes ineffective are, however, undefined. We used a brain slice model to study how focal ictal discharges that were repetitively evoked from the same site, and at precise times, propagate across the cortex. We used Ca²⁺ imaging and simultaneous single/dual cell recordings from pyramidal neurons (PyNs) and different classes of interneurons in rodents, including G42 and GIN transgenic mice expressing the green fluorescence protein in parvalbumin (Pv)‐fast spiking (FS) and somatostatin (Som) interneurons, respectively. We found that these two classes of interneurons fired intensively shortly after ictal discharge generation at the focus. The inhibitory barrages that were recorded in PyNs occurred in coincidence with Pv‐FS, but not with Som interneuron burst discharges. Furthermore, the strength of inhibitory barrages increased or decreased in parallel with increased or decreased firing in Pv‐FS interneurons but not in Som interneurons. A firing impairment of Pv‐FS interneurons caused by a membrane depolarization was found to precede ictal discharge onset in neighbouring pyramidal neurons. This event may account for the collapse of local inhibition that allows spatially defined clusters of PyNs to be recruited into propagating ictal discharges. Our study demonstrates that Pv‐FS interneurons are a major source of the inhibitory barrages that oppose ictal discharge propagation and raises the possibility that targeting Pv‐FS interneurons represents a new therapeutic strategy to prevent the generalization of human focal seizures.