An astrocytic basis of epilepsy

Abstract

Hypersynchronous neuronal firing is a hallmark of epilepsy, but the mechanisms underlying simultaneous activation of multiple neurons remains unknown. Epileptic discharges are in part initiated by a local depolarization shift that drives groups of neurons into synchronous bursting. In an attempt to define the cellular basis for hypersynchronous bursting activity, we studied the occurrence of paroxysmal depolarization shifts after suppressing synaptic activity by TTX and voltage-gated Ca 2+ channel blockers. Here we report that paroxysmal depolarization shifts can be initiated by release of glutamate from extrasynaptic sources or by photolysis of caged Ca 2+ in astrocytes. Two-photon imaging of live exposed cortex revealed that several anti-epileptics, including valproate, gabapentin and phenytoin, reduced the ability of astrocytes to transmit Ca 2+ signaling. Our results reveal an unanticipated key role for astrocytes in seizure activity. As such, these findings identify astrocytes as a proximal target for the treatment of epileptic disorders.Epilepsy is a neurological disorder in which normal brain function is disrupted as a consequence of intensive burst activity from groups of neurons1. Epilepsies result from long-lasting plastic changes in the brain affecting the expression of receptors and channels, and involve sprouting and reorganization of synapses, as well as reactive gliosis2 ,3 . Several lines of evidence suggest a key role of glutamate in the pathogenesis of epilepsy. Local or systemic administration of glutamate agonists triggers excessive neuronal firing, whereas glutamate receptor (GluR) antagonists have anticonvulsant properties 4 . The observation that astrocytes release glutamate via a regulated Ca 2+ dependent mechanism 5-8 prompted us to hypothesize that glutamate released by astrocytes plays a causal role in synchronous firing of large populations of neurons.Paroxysmal depolarization shifts (PDSs) are abnormal prolonged depolarizations with repetitive spiking and are reflected as interictal discharges in the electroencephalogram 2, 3. We report here that glutamate released by astrocytes can trigger PDSs in several models of experimental seizure. A unifying feature of seizure activity was its consistent association Corresponding author: Guo-Feng Tian (Guo-Feng_Tian@URMC.Rochester.edu). * These authors contributed equally to this work. NIH Public Access RESULTS PDSs can be triggered by an action potential-independent mechanismTo examine the cellular mechanism underlying PDSs, we patched CA1 pyramidal neurons in rat hippocampal slices exposed to 4-aminopyridine (4-AP). 4-AP is a K + channel blocker that induces intense electrical discharges in slices9 and seizure activity in experimental animals 10 . All slices exposed to 4-AP (61 slices from 23 rats) exhibited epileptiform bursting activity expressed as transient episodes of neuronal depolarizations eliciting trains of action potentials (Fig. 1a). Bath application of TTX promptly eliminated neuronal firing (Fig. 1b). Unexpectedly, the...

The adenosine kinase hypothesis of epileptogenesis

“…Thus, enhanced or reduced gliotransmission might directly translate into neurological disease. Recently, it was demonstrated that prolonged episodes of neuronal depolarization evoked by astrocytic release of glutamate contributed to epileptiform discharges (Tian et al, 2005). This study provided support for the concept that astrocytes are involved in the initiation, maintenance and spread of seizures.…”

“…This is also true for newer antiepileptic drugs, such as gabapentin and pregabalin, which have recently been demonstrated to act on the α 2 -δ subunit of a voltagegated calcium channel, thus attenuating the calcium flux into neurons (Davies et al, 2007;Field et al, 2007;Taylor et al, 2007). Apart from dysfunction of neuronal networks (Holmes and Ben-Ari, 2003), dysfunction of astrocytes has recently emerged as a critical component of epileptogenesis adding an additional layer of complexity to the underlying disease process (Borges et al, 2006;Tian et al, 2005).…”

Molecular Targets for Antiepileptic Drug Development

“…Recent evidence implicating astrocytes in the generation of epileptic activity suggest that selective targeting of astrocytic gap junctions, such as Cx43, may be a fruitful strategy. 418 The novel benzoylamino benzopyran tonabersat [SB-220453; an analog of the anticonvulsant carabersat (SB-204269) 419 ], which is currently in clinical development for migraine, is believed to block gap junctions. 420 …”

Adenosine dysfunction in astrogliosis: cause for seizure generation?

“…The involvement of astrocytes in the pathogenesis of epileptogenesis is based on findings that astrocytes control synaptic transmission by the vesicular release of glutamate, ATP, and by the release of the NMDA receptor co-agonist D-serine (Haydon and Carmignoto, 2006). Recently, it was demonstrated that prolonged episodes of neuronal depolarization evoked by astrocytic release of glutamate contributed to epileptiform discharges (Tian et al, 2005). Thus, astrocyte dysfunction appears to be a major contributing factor to epileptogenesis.…”