Induction of Hippocampal Long-Term Depression Requires Release of Ca2+from Separate Presynaptic and Postsynaptic Intracellular Stores

Abstract

Studies have suggested that an increase in intracellular [Ca 2+] is necessary for the induction of both long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission, and that release of Ca 2+from intracellular storage pools can be necessary to induce LTP. We investigated whether release of Ca 2+from intracellular stores also is required for the induction of LTD at Schaffer collateral–CA1 synapses in hippocampal slices. Both thapsigargin (1 μ m) and cyclopiazonic acid (1 μ m), compounds that deplete all intracellular Ca 2+pools by blocking ATP-dependent Ca 2+uptake into intracellular compartments, blocked the induction, but not maintenance, of LTD by low-frequency stimulation (LFS) (1 Hz/15 min) without affecting baseline synaptic transmission. Washout of the reversible inhibitor cyclopiazonic acid restored the ability to induce LTD. In contrast, thapsigargin did not block depotentiation of LTP by 1 Hz LFS, suggesting that LTP causes a reduction in the threshold [Ca 2+] necessary for LTD. Selective depletion of the ryanodine receptor-gated Ca 2+pool by bath application of ryanodine (10 μ m) also blocked the induction of LTD, indicating a requirement for Ca 2+-induced Ca 2+release. Impalement of CA1 pyramidal neurons with microelectrodes containing thapsigargin (500 n m to 200 μ m) prevented the induction of LTD at synapses on that neuron without blocking LTD in the rest of the slice. In contrast, similar filling of CA1 pyramidal neurons with ryanodine (2 μ m to 5 m m) did not block the induction of LTD. From these data, we conclude that the induction of LTD requires release of Ca 2+both from a presynaptic ryanodine-sensitive pool and from postsynaptic(presumably IP 3-gated) stores.