For induction of long-term depression (LTD), mechanisms dependent on N-methyl-D-aspartate receptors (NMDARs) and on intracellular calcium stores have been separately known. How these two mechanisms coexist at the same synapses is not clear. Here, induction of LTD at hippocampal Schaffer collateral-to-CA1 pyramidal cell synapses was shown to depend on NMDARs throughout the theoretically predicted activation range for LTD induction. With stimulation at 1 Hz, the largest LTD was induced in a store-independent manner. With stimulation at 0.5 and 2.0 Hz the induced LTD was much smaller, and dependence on calcium stores appeared. Under caffeine application, an enlarged LTD was induced with 0.5 Hz stimulation. Postsynaptic blockade of ryanodine receptors prevented this caffeine-induced enhancement of LTD. It is therefore suggested that calcium release from calcium stores facilitated by caffeine contributed to the LTD enhancement, and that the caffeine effect was exerted on the postsynaptic side. Induction of this enhanced LTD was resistant to NMDAR blockade. We thus propose that the store-dependent mechanism for LTD induction is dormant at the centre of the theoretically predicted activation range for LTD induction, but operates at the fringes of this activation range, with its contribution more emphasized when ample calcium release occurs.

Specific contributions of voltage-dependent calcium channels (VDCCs) to induction of long-term depression (LTD) have not been thoroughly elucidated. The present study examined roles of T- and L-type VDCCs in N-methyl-D-aspartate (NMDA) receptor-dependent LTD induced at several different levels of synaptic activation (0.5- to 10-Hz presynaptic stimulations) at Schaffer collateral-CA1 synapses in rat hippocampal slices. Blockade of T-type VDCCs with nickel ions failed to change LTD magnitude at all levels of stimulation. However, blockade of L-type VDCCs reduced LTD in response to stimulation at 1 and 2 Hz and, conversely, enhanced LTD at a lower frequency (0.5 Hz). The enhancement of 0.5-Hz LTD under L-type VDCC blockade was shown pharmacologically to depend on NMDA receptors (NMDARs) and intracellular Ca(2+) release. Calcium imaging revealed that contribution of L-type VDCC-mediated calcium influx to the total calcium increase was greater during 0.5-Hz stimulation than during 1.0-Hz stimulation. This finding, combined with the reported suppression of NMDARs mediated by L-type VDCCs, may be relevant to the present enhancement of 0.5-Hz LTD due to L-type VDCC blockade.

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