Non-Ionotropic NMDA Receptor Signaling in Mechanistically Distinct Forms of Hippocampal Depotentiation

The reversal of learning-induced synaptic potentiation through depotentiation may be important in certain types of forgetting. Here, we evaluated how synaptic plasticity induced by different stimuli in the hippocampus is affected by mechanistically distinct forms of depotentiation. In hippocampal slices obtained from male and female mice, we artificially induced long-term potentiation (LTP) using either a temporally spaced or compressed stimulation pattern. Using a combination of electrophysiology and protein quantification approaches, we found divergent molecular pathways recruited during depotentiation of spaced and compressed LTP. Depotentiation of both forms of LTP required glutamatergic activation of the N-methyl-d-aspartate receptor (NMDAR). However, depotentiation of compressed, but not spaced, LTP shared a requirement with long-term depression for intracellular non-ionotropic NMDAR (NI-NMDAR) signaling cascades mediated by the C-terminal domain of GluN1. Downstream of NMDAR signaling, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor phosphorylation was also differentially modified during depotentiation of spaced and compressed LTP. Finally, we found that depotentiation of spaced but not compressed LTP required synaptic Arc. Altogether, we identify the role of NI-NMDAR signaling in synaptic depotentiation. Additionally, we reveal two mechanistically distinct forms of NMDAR-dependent depotentiation that can be selectively induced after different temporal patterns of LTP induction. Our findings have important implications for the regulation of physiological and pathological forgetting.