ABSTRACT
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.
Subject(s)
Caspases/physiology , Hippocampus/drug effects , Long-Term Potentiation/physiology , Action Potentials/drug effects , Action Potentials/physiology , Animals , Calpain/pharmacology , Caspase 3 , Caspase Inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Dipeptides/pharmacology , Electric Stimulation , Enzyme Precursors/metabolism , Enzyme Precursors/physiology , Hippocampus/anatomy & histology , Hippocampus/physiology , In Vitro Techniques , Ketones/pharmacology , Long-Term Potentiation/drug effects , Male , Oligopeptides/pharmacology , Rats , Time FactorsABSTRACT
Postnatal changes in population spike (PS) amplitudes and caspase-3 activity were compared in the hippocampi of control rats and experimental animals subjected to a brief footshock on postnatal day (PD) 13. Footshock induced an increase in maximal PS amplitudes during the early period (from PD 14 to PD 16), however, the difference between stressed and control animals gradually decreased with age up to PD 21. No difference between hippocampal caspase-3 activity in control and footshock groups was revealed within the PD 14-17. However, caspase-3 activity in the latter group was significantly lower over the next period of postnatal development (PD 18-21). PS amplitudes in the slices of the footshock group significantly increased over PD 22-27. We suggest that footshock activates the development of hippocampal circuitry during early phases, this phenomenon mediating enhanced responsiveness as a result of an increased production of synaptic connections and related decrease in neuronal loss.
