Serine proteases such as tissue plasminogen activator (tPA), thrombin and neuropsin influence hippocampal plasticity involved in learning and memory by facilitating both synaptic remodelling and long-term potentiation. Given our previous findings that trypsin and its receptor, protease-activated receptor-2 (PAR2), are both highly expressed in pyramidal neurons of the hippocampus and that activation of PAR2 attenuates 'pathogenic' plasticity related to epilepsy, we wished to determine the role for PAR2 in normal, non-pathological hippocampal plasticity related to learning and memory. In a strain of rat that show high basal levels of anxiety, the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), peripheral administration of the PAR2 peptide agonist, SLIGRL (1.5 mg/kg s.c.), induced distinct deficits in experience-dependent learning both in the test-retest paradigm of the elevated-plus maze and in the Morris water maze. In separate, conscious rats with indwelling intra-cerebroventricular cannulae, SLIGRL rapidly appeared in cerebrospinal fluid (CSF) following peripheral administration and had a half-life in CSF of approximately 25 min. These results suggest that activation of central PAR2 with brain accessible peptide agonists causes a temporary deficit in the formation and/or recollection of experience-dependent learning and memory.