title: 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 using tetrodotoxin (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 showed that several antiepileptic agents, including valproate, gabapentin and phenytoin, reduced the ability of astrocytes to transmit Ca(2+) signaling. Our results show 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.
authors.affiliation: Center for Aging and Developmental Biology, Department of Neurosurgery, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA.
authors.forename: Guo-Feng
authors.initials: GF
authors.lastname: Tian
authors.forename: Hooman
authors.initials: H
authors.lastname: Azmi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Takano
authors.forename: Qiwu
authors.initials: Q
authors.lastname: Xu
authors.forename: Weiguo
authors.initials: W
authors.lastname: Peng
authors.forename: Jane
authors.initials: J
authors.lastname: Lin
authors.forename: NancyAnn
authors.initials: N
authors.lastname: Oberheim
authors.forename: Nanhong
authors.initials: N
authors.lastname: Lou
authors.forename: Xiaohai
authors.initials: X
authors.lastname: Wang
authors.forename: H Ronald
authors.initials: HR
authors.lastname: Zielke
authors.forename: Jian
authors.initials: J
authors.lastname: Kang
authors.forename: Maiken
authors.initials: M
authors.lastname: Nedergaard
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D004827:Epilepsy / Q000503:physiopathology*; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus; D010782:Photolysis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000927:Anticonvulsants; D018698:Glutamic Acid