Chronic administration of a thiol-proteinase inhibitor blocks long-term potentiation of synaptic responses

It has been proposed that activation of a calcium-sensitive protease (calpain) is a crucial step in the induction of long-term potentiation (LTP). To test this hypothesis, we used chronic recording techniques to measure the effects of intraventricular infusion of leupeptin, a calpain inhibitor, on LTP in the hippocampus. Rats implanted bilaterally with stimulating electrodes in the Schaffer-commissural system and one recording electrode in the apical dendrites of field CA1 were fitted with osmotic mini-pumps delivering either leupeptin (20 mg/ml) or saline at a rate of 0.5 microliter/h into the lateral ventricle. Short bursts of high-frequency stimulation with the bursts delivered at 5/s were used to induce LTP in those animals which had stable responses for several days. Rats in the saline group (n = 11) exhibited an immediate LTP effect that remained in place over successive days of testing, while only 3 of 13 leupeptin treated animals showed evidence of LTP 24 h after high-frequency stimulation, and in only one of those was a sizeable effect recorded over several days. The average change in responses at the 24-h test point was +33% for the controls and +4% for the leupeptin group (P less than 0.01). The block of LTP induction was reversible, since high-frequency stimulation applied after disconnecting the pumps led to a robust LTP effect that lasted for several days in 6 of 7 animals tested. There were no detectable differences in baseline responses in the presence and absence of leupeptin.