Nature Medicine
11, 973 - 981 (2005)
Published online: 14 August 2005; | doi:10.1038/nm1277
An astrocytic basis of epilepsyGuo-Feng Tian1, 6, Hooman Azmi2, 6, Takahiro Takano1, Qiwu Xu1, Weiguo Peng1, Jane Lin3, NancyAnn Oberheim1, Nanhong Lou1, Xiaohai Wang1, H Ronald Zielke4, Jian Kang5
& Maiken Nedergaard11
Center for Aging and Developmental Biology, Department of Neurosurgery, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA. 2
Department of Neurosurgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 90 Bergen Street, Newark, New Jersey 07103, USA. 3
Department of Pathology, New York Medical College, 30 Sunshine Cottage Road, Valhalla, New York 10595, USA. 4
Department of Pediatrics, University of Maryland, 655 W. Baltimore Street, Baltimore, Maryland 21201, USA. 5
Department of Cell Biology, New York Medical College, 30 Sunshine Cottage Road, Valhalla, New York 10595, USA. 6
These authors contributed equally to this work.
Correspondence should be addressed to Guo-Feng Tian guo-feng_tian@urmc.rochester.edu 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 Ca2+ channel blockers. Here we report that paroxysmal depolarization shifts can be initiated by release of glutamate from extrasynaptic sources or by photolysis of caged Ca2+ 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 Ca2+ 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.
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