title: Protease-activated receptor-1 modulates hippocampal memory formation and synaptic plasticity.
abstract: Protease-activated receptor-1 (PAR1) is an unusual G-protein coupled receptor (GPCR) that is activated through proteolytic cleavage by extracellular serine proteases. Although previous work has shown that inhibiting PAR1 activation is neuroprotective in models of ischemia, traumatic injury, and neurotoxicity, surprisingly little is known about PAR1's contribution to normal brain function. Here, we used PAR1-/- mice to investigate the contribution of PAR1 function to memory formation and synaptic function. We demonstrate that PAR1-/- mice have deficits in hippocampus-dependent memory. We also show that while PAR1-/- mice have normal baseline synaptic transmission at Schaffer collateral-CA1 synapses, they exhibit severe deficits in N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). Mounting evidence indicates that activation of PAR1 leads to potentiation of NMDAR-mediated responses in CA1 pyramidal cells. Taken together, this evidence and our data suggest an important role for PAR1 function in NMDAR-dependent processes subserving memory formation and synaptic plasticity.
authors.affiliation: Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Antoine G
authors.initials: AG
authors.lastname: Almonte
authors.forename: Laura H
authors.initials: LH
authors.lastname: Qadri
authors.forename: Faraz A
authors.initials: FA
authors.lastname: Sultan
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Watson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Mount
authors.forename: Gavin
authors.initials: G
authors.lastname: Rumbaugh
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001703:Biophysics; D003213:Conditioning, Psychological / Q000502:physiology; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005239:Fear / Q000502:physiology; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics*; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000172:deficiency / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000235:genetics* / Q000502:physiology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione