Caspase activity is essential for long-term potentiation

Slices from rat hippocampus were incubated with the caspase-3 inhibitor N-benzyloxycarbonyl-Asp-Glu-Val-Asp fluoromethylketone (Z-DEVD-FMK) or with the inactive peptide N-benzyloxycarbonyl-Phe-Ala fluoromethylketone (Z-Phe-Ala-FMK) for 30 min. The peptides changed neither input-output curves nor paired-pulse effects at 70-msec interpulse intervals, nor amplitudes of pop spikes in the CA1 region 1.0-6.9 hr after the incubation. Slices taken 1.0-1.4 hr after Z-DEVD-FMK or inactive peptide treatment demonstrated similar long-term potentiation (LTP) curves; however, LTP was suppressed significantly (P<0.001) 1.5-3.4 hr after Z-DEVD-FMK treatment when compared to the corresponding inactive peptide group. LTP magnitude correlated with time after Z-DEVD-FMK (r= -0.74; P<0.02) but did not depend on time after the inactive peptide treatment. After 3.5 hr, LTP was blocked completely. Z-DEVD-FMK did not have a significant effect on presynaptic function. The results are the first evidence that inhibition of caspase-3 significantly decreases or fully blocks LTP in the CA1 region and suggest that caspase-3 is essential for LTP. Candidate caspase-3 substrates that may be cleaved for LTP induction and maintenance are discussed.