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Ca2+ released from presynaptic and postsynaptic intracellular stores plays important roles in activity-dependent synaptic plasticity, including long-term depression (LTD) of synaptic strength. At Schaffer collateral-CA1 synapses in the hippocampus, presynaptic ryanodine receptor-gated stores appear to mobilize some of the Ca2+ necessary to induce LTD. Cyclic ADP-ribose (cADPR) has recently been proposed as an endogenous activator of ryanodine receptors in sea urchin eggs and several mammalian cell types. Here, we provide evidence that cADPR-mediated signaling pathways play a key role in inducing LTD. We show that biochemical production of cGMP increases cADPR concentration in hippocampal slices in vitro, and that blockade of cGMP-dependent protein kinase, cADPR receptors, or ryanodine-sensitive Ca2+ stores each prevent the induction of LTD at Schaffer collateral-CA1 synapses. A lack of effect of postsynaptic infusion of either cADPR antagonist indicates a probable presynaptic site of action.

Original publication




Journal article


Proc Natl Acad Sci U S A

Publication Date





4061 - 4066


ADP-ribosyl Cyclase, ADP-ribosyl Cyclase 1, Adenosine Diphosphate Ribose, Animals, Antigens, CD, Antigens, Differentiation, Calcium, Cyclic ADP-Ribose, Entorhinal Cortex, Excitatory Postsynaptic Potentials, Female, Hippocampus, In Vitro Techniques, Isoquinolines, Male, Membrane Glycoproteins, Models, Neurological, NAD+ Nucleosidase, Neuronal Plasticity, Neurons, Rats, Rats, Sprague-Dawley, Ryanodine, Signal Transduction, Sulfonamides, Synapses, Synaptic Transmission