An astrocytic basis of epilepsy

Guo Feng Tian; Hooman Azmi; Takahiro Takano; Qiwu Xu; Weiguo Peng; Jane Lin; Nancy Ann Oberheim; Nanhong Lou; Xiaohai Wang; H. Ronald Zielke; Jian Kang; Maiken Nedergaard

doi:10.1038/nm1277

An astrocytic basis of epilepsy

Guo Feng Tian
, Hooman Azmi
, Takahiro Takano
, Qiwu Xu
, Weiguo Peng
, Jane Lin
, Nancy Ann Oberheim
, Nanhong Lou
, Xiaohai Wang
, H. Ronald Zielke
, Jian Kang
, Maiken Nedergaard

School of Medicine

Hackensack Meridian School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	973-981
Number of pages	9
Journal	Nature medicine
Volume	11
Issue number	9
DOIs	https://doi.org/10.1038/nm1277
State	Published - Sep 2005

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1038/nm1277

Cite this

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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 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.",

author = "Tian, \{Guo Feng\} and Hooman Azmi and Takahiro Takano and Qiwu Xu and Weiguo Peng and Jane Lin and Oberheim, \{Nancy Ann\} and Nanhong Lou and Xiaohai Wang and Zielke, \{H. Ronald\} and Jian Kang and Maiken Nedergaard",

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T1 - An astrocytic basis of epilepsy

AU - Tian, Guo Feng

AU - Azmi, Hooman

AU - Takano, Takahiro

AU - Xu, Qiwu

AU - Peng, Weiguo

AU - Lin, Jane

AU - Oberheim, Nancy Ann

AU - Lou, Nanhong

AU - Wang, Xiaohai

AU - Zielke, H. Ronald

AU - Kang, Jian

AU - Nedergaard, Maiken

PY - 2005/9

Y1 - 2005/9

N2 - 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.

AB - 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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U2 - 10.1038/nm1277

DO - 10.1038/nm1277

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SN - 1078-8956

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SP - 973

EP - 981

JO - Nature medicine

JF - Nature medicine

IS - 9

ER -

An astrocytic basis of epilepsy

Abstract

ASJC Scopus subject areas

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