Journal
NATURE MEDICINE
Volume 11, Issue 9, Pages 973-981Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm1277
Keywords
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Funding
- NICHD NIH HHS [HD16596] Funding Source: Medline
- NINDS NIH HHS [R01 NS030007, NS38073, R01 NS038073, R01 NS039997, NS39997, NS30007] Funding Source: Medline
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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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