TY - JOUR
T1 - Thrombin regulation of synaptic plasticity
T2 - Implications for physiology and pathology
AU - Maggio, Nicola
AU - Itsekson, Zeev
AU - Dominissini, Dan
AU - Blatt, Ilan
AU - Amariglio, Ninette
AU - Rechavi, Gideon
AU - Tanne, David
AU - Chapman, Joab
PY - 2013/9
Y1 - 2013/9
N2 - 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.
AB - 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.
KW - Extracellular proteases
KW - Hippocampus
KW - LTP
KW - PAR1
KW - Synaptic plasticity
KW - Thrombin
UR - http://www.scopus.com/inward/record.url?scp=84881367333&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2013.02.011
DO - 10.1016/j.expneurol.2013.02.011
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AN - SCOPUS:84881367333
SN - 0014-4886
VL - 247
SP - 595
EP - 604
JO - Experimental Neurology
JF - Experimental Neurology
ER -