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The Journal of Neuroscience, October 3, 2007, 27(40):10674-10684; doi:10.1523/JNEUROSCI.2001-07.2007

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Neurobiology of Disease
Enhanced Astrocytic Ca²⁺ Signals Contribute to Neuronal Excitotoxicity after Status Epilepticus

Shinghua Ding,^1 * Tommaso Fellin,^1 * Yingzi Zhu,^1 * So-Young Lee,¹ Yves P. Auberson,⁴ David F. Meaney,² Douglas A. Coulter,^1,3 Giorgio Carmignoto,⁵ and Philip G. Haydon¹

¹Silvio Conte Center for Integration at the Tripartite Synapse, Department of Neuroscience, University of Pennsylvania School of Medicine, ²Department of Bioengineering, University of Pennsylvania, and ³Departments of Pediatrics and Neurology, University of Pennsylvania School of Medicine and the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, ⁴Novartis Institutes for BioMedical Research, Novartis Pharma AG, 4002 Basel, Switzerland, and ⁵Instituto Consiglio Nazionale delle Ricerche di Neuroscienze and Dipartimento di Scienze Biomediche Sperimentali, Università di Padova, 35121 Padova, Italy

Correspondence should be addressed to Philip G. Haydon, Silvio Conte Center for Integration at the Tripartite Synapse, Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. Email: pghaydon{at}mail.med.upenn.edu

Status epilepticus (SE), an unremitting seizure, is known to cause a variety of traumatic responses including delayed neuronal death and later cognitive decline. Although excitotoxicity has been implicated in this delayed process, the cellular mechanisms are unclear. Because our previous brain slice studies have shown that chemically induced epileptiform activity can lead to elevated astrocytic Ca²⁺ signaling and because these signals are able to induce the release of the excitotoxic transmitter glutamate from these glia, we asked whether astrocytes are activated during status epilepticus and whether they contribute to delayed neuronal death in vivo. Using two-photon microscopy in vivo, we show that status epilepticus enhances astrocytic Ca²⁺ signals for 3 d and that the period of elevated glial Ca²⁺ signaling is correlated with the period of delayed neuronal death. To ask whether astrocytes contribute to delayed neuronal death, we first administered antagonists which inhibit gliotransmission: MPEP [2-methyl-6-(phenylethynyl)pyridine], a metabotropic glutamate receptor 5 antagonist that blocks astrocytic Ca²⁺ signals in vivo, and ifenprodil, an NMDA receptor antagonist that reduces the actions of glial-derived glutamate. Administration of these antagonists after SE provided significant neuronal protection raising the potential for a glial contribution to neuronal death. To test this glial hypothesis directly, we loaded Ca²⁺ chelators selectively into astrocytes after status epilepticus. We demonstrate that the selective attenuation of glial Ca²⁺ signals leads to neuronal protection. These observations support neurotoxic roles for astrocytic gliotransmission in pathological conditions and identify this process as a novel therapeutic target.

Key words: astrocyte; NMDA; metabotropic glutamate receptor; epilepsy; calcium; astrocytic glutamate release

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Received May 2, 2007; revised Aug. 14, 2007; accepted Aug. 18, 2007.

Correspondence should be addressed to Philip G. Haydon, Silvio Conte Center for Integration at the Tripartite Synapse, Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. Email: pghaydon{at}mail.med.upenn.edu

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