Protease‐activated receptor‐1 modulates hippocampal memory formation and synaptic plasticity

Protease‐activated receptor‐1 ( PAR 1) 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 PAR 1 activation is neuroprotective in models of ischemia, traumatic injury, and neurotoxicity, surprisingly little is known about PAR 1's contribution to normal brain function. Here, we used PAR 1−/− mice to investigate the contribution of PAR 1 function to memory formation and synaptic function. We demonstrate that PAR 1−/− mice have deficits in hippocampus‐dependent memory. We also show that while PAR 1−/− mice have normal baseline synaptic transmission at Schaffer collateral‐ CA 1 synapses, they exhibit severe deficits in N‐methyl‐ d ‐aspartate receptor ( NMDAR )‐dependent long‐term potentiation ( LTP ). Mounting evidence indicates that activation of PAR 1 leads to potentiation of NMDAR ‐mediated responses in CA 1 pyramidal cells. Taken together, this evidence and our data suggest an important role for PAR 1 function in NMDAR ‐dependent processes subserving memory formation and synaptic plasticity.