title: Thrombin regulation of synaptic plasticity: implications for physiology and pathology.
abstract: Thrombin, a serine protease involved in the coagulation cascade has been recently shown to affect neuronal function following blood-brain barrier breakdown. Several lines of evidence have shown that thrombin may exist in the brain parenchyma under normal physiological conditions, yet its role in normal brain functions and synaptic transmission has not been established. In an attempt to shed light on the physiological functions of thrombin and Protease Activated Receptor 1 (PAR1) in the brain, we studied the effects of thrombin and a PAR1 agonist on long term potentiation (LTP) in mice hippocampal slices. Surprisingly, different concentrations of thrombin affect LTP through different molecular routes converging on PAR1. High thrombin concentrations induced an NMDA dependent, slow onset LTP, whereas low concentrations of thrombin promoted a VGCCs, mGluR-5 dependent LTP through activated Protein C (aPC). Remarkably, aPC facilitated LTP by activating PAR1 through an Endothelial Protein C Receptor (EPCR)-mediated mechanism which involves intracellular calcium stores. These findings reveal a novel mechanism by which PAR1 may regulate the threshold for synaptic plasticity in the hippocampus and provide additional insights into the role of this receptor in normal and pathological conditions.
authors: Talpiot Medical Leadership Program, The Chaim Sheba Medical Center, 52621 Tel HaShomer, Israel. nicola.maggio@sheba.health.gov.il
authors: Nicola
authors: N
authors: Maggio
authors: Zeev
authors: Z
authors: Itsekson
authors: Dan
authors: D
authors: Dominissini
authors: Ilan
authors: I
authors: Blatt
authors: Ninette
authors: N
authors: Amariglio
authors: Gideon
authors: G
authors: Rechavi
authors: David
authors: D
authors: Tanne
authors: Joab
authors: J
authors: Chapman
mesh_terms: D000818:Animals; D001703:Biophysics; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D000074283:Endothelial Protein C Receptor; D005341:Fibrinolysin / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors
chemical_list: D000074283:Endothelial Protein C Receptor; C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; C080248:Procr protein, mouse; D011758:Pyrroles; D011799:Quinazolines; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D016202:N-Methylaspartate; D013917:Thrombin; D005341:Fibrinolysin; D010751:Phosphopyruvate Hydratase; D010975:Platelet Aggregation Inhibitors
keywords: Extracellular proteases; Hippocampus; LTP; PAR1; Synaptic plasticity; Thrombin