title: Thrombin induces ischemic LTP (iLTP): implications for synaptic plasticity in the acute phase of ischemic stroke.
abstract: Acute brain ischemia modifies synaptic plasticity by inducing ischemic long-term potentiation (iLTP) of synaptic transmission through the activation of N-Methyl-D-aspartate receptors (NMDAR). Thrombin, a blood coagulation factor, affects synaptic plasticity in an NMDAR dependent manner. Since its activity and concentration is increased in brain tissue upon acute stroke, we sought to clarify whether thrombin could mediate iLTP through the activation of its receptor Protease-Activated receptor 1 (PAR1). Extracellular recordings were obtained in CA1 region of hippocampal slices from C57BL/6 mice. In vitro ischemia was induced by acute (3 minutes) oxygen and glucose deprivation (OGD). A specific ex vivo enzymatic assay was employed to assess thrombin activity in hippocampal slices, while OGD-induced changes in prothrombin mRNA levels were assessed by (RT)qPCR. Upon OGD, thrombin activity increased in hippocampal slices. A robust potentiation of excitatory synaptic strength was detected, which occluded the ability to induce further LTP. Inhibition of either thrombin or its receptor PAR1 blocked iLTP and restored the physiological, stimulus induced LTP. Our study provides important insights on the early changes occurring at excitatory synapses after ischemia and indicates the thrombin/PAR1 pathway as a novel target for developing therapeutic strategies to restore synaptic function in the acute phase of ischemic stroke.
authors.affiliation: Department of Neurology, The Chaim Sheba Medical Center, Tel HaShomer, Israel.
authors.forename: Efrat Shavit
authors.initials: ES
authors.lastname: Stein
authors.affiliation: Department of Neurology, The Chaim Sheba Medical Center, Tel HaShomer, Israel.
authors.forename: Zeev
authors.initials: Z
authors.lastname: Itsekson-Hayosh
authors.affiliation: 1] Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel [2] Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Aronovich
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Reisner
authors.affiliation: Department of Neurology, The Chaim Sheba Medical Center, Tel HaShomer, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Bushi
authors.affiliation: Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Chaim G
authors.initials: CG
authors.lastname: Pick
authors.affiliation: 1] Department of Neurology, The Chaim Sheba Medical Center, Tel HaShomer, Israel [2] Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Tanne
authors.affiliation: 1] Department of Neurology, The Chaim Sheba Medical Center, Tel HaShomer, Israel [2] Department of Neurology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Joab
authors.initials: J
authors.lastname: Chapman
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Vlachos
authors.affiliation: 1] Department of Neurology, The Chaim Sheba Medical Center, Tel HaShomer, Israel [2] Talpiot Medical Leadership Program, The Chaim Sheba Medical Center, Tel HaShomer, Israel.
authors.forename: Nicola
authors.initials: N
authors.lastname: Maggio
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000378:metabolism* / Q000473:pathology; D017774:Long-Term Potentiation; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate; D013917:Thrombin / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D044463:Receptor, PAR-1; D016194:Receptors, N-Methyl-D-Aspartate; D013917:Thrombin