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...

Movement disorders, such as Parkinson's disease, tremor, and dystonia, are among the most common neurological conditions and affect millions of patients. Although medications are the mainstay of therapy for movement disorders, neurosurgery has played an important role in their management for the past 50 years. Surgery is now a viable and safe option for patients with medically intractable Parkinson's disease, essential tremor, and dystonia. In this article, we provide a review of the history, neurocircuitry, indication, technical aspects, outcomes, complications, and emerging neurosurgical approaches for the treatment of movement disorders.

Therapeutic/care management, level III.