title: The anticoagulant activated protein C (aPC) promotes metaplasticity in the hippocampus through an EPCR-PAR1-S1P1 receptors dependent mechanism.
abstract: Thrombin and other clotting factors regulate long-term potentiation (LTP) in the hippocampus through the activation of the protease activated receptor 1 (PAR1) and consequent potentiation of N-methyl-d-aspartate receptor (NMDAR) functions. We have recently shown that the activation of PAR1 either by thrombin or the anticoagulant factor activated protein C (aPC) has differential effects on LTP. While thrombin activation of PAR1 induces an NMDAR-mediated slow onset LTP, which saturates the ability to induce further LTP in the exposed network, aPC stimulation of PAR1 enhances tetanus induced LTP through a voltage-gated calcium channels mediated mechanism. In this study, we addressed the mechanisms by which aPC enhances LTP in hippocampal slices. Using extracellular recordings, we show that a short tetanic stimulation, which does not induce LTP, is able to enhance plasticity in the presence of aPC through a mechanism that requires the activation of sphingosine-1 phosphate receptor 1 and intracellular Ca(2+) stores. These data identify aPC as a "metaplastic molecule", capable of shifting the threshold of LTP towards further potentiation. Our findings propose novel strategies to enhance plasticity in neurological diseases associated with the breakdown of the blood brain barrier and alterations in synaptic plasticity.
authors.affiliation: Talpiot Medical Leadership Program, The Chaim Sheba Medical Center, Tel HaShomer, Israel; Department of Neurology and the J. Sagol Neuroscience Center, The Chaim Sheba Medical Center, Tel HaShomer, Israel.
authors.forename: Nicola
authors.initials: N
authors.lastname: Maggio
authors.forename: Zeev
authors.initials: Z
authors.lastname: Itsekson
authors.forename: Benno
authors.initials: B
authors.lastname: Ikenberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Strehl
authors.forename: Andreas
authors.initials: A
authors.lastname: Vlachos
authors.forename: Ilan
authors.initials: I
authors.lastname: Blatt
authors.forename: David
authors.initials: D
authors.lastname: Tanne
authors.forename: Joab
authors.initials: J
authors.lastname: Chapman
mesh_terms: D000818:Animals; D001779:Blood Coagulation Factors / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011486:Protein C / Q000378:metabolism*; D044463:Receptor, PAR-1 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D046509:Tissue Culture Techniques
chemical_list: D001779:Blood Coagulation Factors; D011486:Protein C; D044463:Receptor, PAR-1; D011956:Receptors, Cell Surface; D049349:Receptors, Lysosphingolipid; D016194:Receptors, N-Methyl-D-Aspartate; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C091963:activated protein C receptor; D002118:Calcium
keywords: Ca2+ stores; LTP; PAR1; S1P1; activated protein C; lipid signaling; metaplasticity