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An astrocytic basis of epilepsy

Nature Medicine volume 11, pages 973–981 (2005)Cite this article

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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Figure 1: Synaptic activity is not required for PDSs in hippocampal slices evoked by 4-AP.
Figure 2: PDSs are mediated by release of glutamate from action potential–independent sources.
Figure 3: Spontaneous depolarization shifts in four experimental models of epilepsy.
Figure 4: Epileptogenic agents evoke oscillatory increases in astrocytic cytosolic Ca2+ concentration, which precedes PDSs, and PDSs are spatially confined to small domains.
Figure 5: Astrocytes are the primary source of glutamate in experimental seizure.
Figure 6: Experimental seizures in adult mice and the effect of antiepileptic agents on astrocytic Ca2+ signaling.

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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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Author notes

  1. Guo-Feng Tian and Hooman Azmi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Center for Aging and Developmental Biology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, 14642, New York, USA

    Guo-Feng Tian, Takahiro Takano, Qiwu Xu, Weiguo Peng, NancyAnn Oberheim, Nanhong Lou, Xiaohai Wang & Maiken Nedergaard

  2. Department of Neurosurgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 90 Bergen Street, Newark, 07103, New Jersey, USA

    Hooman Azmi

  3. Department of Pathology, New York Medical College, 30 Sunshine Cottage Road, Valhalla, 10595, New York, USA

    Jane Lin

  4. Department of Pediatrics, University of Maryland, 655 W. Baltimore Street, Baltimore, 21201, Maryland, USA

    H Ronald Zielke

  5. Department of Cell Biology, New York Medical College, 30 Sunshine Cottage Road, Valhalla, 10595, New York, USA

    Jian Kang

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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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