An astrocytic basis of epilepsy.
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.
Tian
Guo-Feng
GF
Center for Aging and Developmental Biology, Department of Neurosurgery, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA.
Azmi
Hooman
H
Takano
Takahiro
T
Xu
Qiwu
Q
Peng
Weiguo
W
Lin
Jane
J
Oberheim
NancyAnn
N
Lou
Nanhong
N
Wang
Xiaohai
X
Zielke
H Ronald
HR
Kang
Jian
J
Nedergaard
Maiken
M
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
D000927:Anticonvulsants; D018698:Glutamic Acid