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 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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Acknowledgements
We thank S. Goldman, S. Rothman, H. Yeh, T. Obrenovitch and E. Vates for their comments. This work was supported in part by US National Institutes of Health and National Institute of Neurological Disorders and Stroke grants NS30007 and NS38073 (to M.N.), NS39997 (to J.K.) and HD16596 (to H.R.Z.).
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Tian, GF., Azmi, H., Takano, T. et al. An astrocytic basis of epilepsy. Nat Med 11, 973–981 (2005). https://doi.org/10.1038/nm1277
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DOI: https://doi.org/10.1038/nm1277
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