title: Enhanced astrocytic Ca2+ signals contribute to neuronal excitotoxicity after status epilepticus.
abstract: 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.
authors.affiliation: Silvio Conte Center for Integration at the Tripartite Synapse, Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Shinghua
authors.initials: S
authors.lastname: Ding
authors.forename: Tommaso
authors.initials: T
authors.lastname: Fellin
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Zhu
authors.forename: So-Young
authors.initials: SY
authors.lastname: Lee
authors.forename: Yves P
authors.initials: YP
authors.lastname: Auberson
authors.forename: David F
authors.initials: DF
authors.lastname: Meaney
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Coulter
authors.forename: Giorgio
authors.initials: G
authors.lastname: Carmignoto
authors.forename: Philip G
authors.initials: PG
authors.lastname: Haydon
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004533:Egtazic Acid / Q000031:analogs & derivatives; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010862:Pilocarpine; D010880:Piperidines / Q000494:pharmacology; D017470:Receptors, Glutamate / Q000502:physiology; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D013997:Time Factors
chemical_list: D000927:Anticonvulsants; D002614:Chelating Agents; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D017470:Receptors, Glutamate; D010862:Pilocarpine; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; C010739:ifenprodil; D002118:Calcium