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 NMDA receptor (NMDAR). However, depotentiation of compressed, but not spaced, LTP shared a requirement with long-term depression for intracellular non-ionotropic NMDAR signaling cascades mediated by the C-terminal domain of GluN1. Downstream of NMDAR signaling, AMPA 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 a role for non-ionotropic 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. Significance statement Synaptic depotentiation, the reversal of learning-associated synaptic potentiation, is an important mechanism of forgetting. This study uncovers divergent signaling pathways mediating depotentiation in the hippocampus. We reveal that the type of long-term potentiation (LTP) induced can bias signaling pathways downstream of NMDA receptor activation during depotentiation. Specifically, we show divergent requirements for non-ionotropic GluN1 C-terminal domain interactions in depotentiation of LTP induced using temporally compressed versus spaced patterned activity. Further, depotentiation of spaced and compressed LTP are associated with unique biochemical signatures, including AMPA receptor phosphorylation states, consistent with divergent molecular mechanisms that act to dampen synaptic responses. Our results illuminate fundamental mechanisms that govern plasticity associated with forgetting, with implications for memory preservation in disease states.