Making memories malleable: The role and regulation of synaptic depotentiation in engram alteration

Activity-dependent increases in synaptic strength, including long-term potentiation, are involved in learning to facilitate memory encoding and recall. The reversal of long-term potentiation, termed synaptic depotentiation, has also been observed in brain slices and in behaving animals; yet its precise role in memory processing is unclear. Here, we review functional and structural evidence for synaptic depotentiation in memory processes that support flexible and adaptive behaviour in rodents. We present evidence that depotentiation serves to weaken synapses potentiated during prior learning events to facilitate active forgetting and memory destabilization. The demonstrated ability for prior synaptic activity and neuromodulatory inputs to regulate depotentiation may contribute to scenarios where certain memories resist forgetting or modification. Understanding the synaptic mechanisms that give rise to memory flexibility enables the development of better in vitro models to provide a more accurate conceptualization of the nature of forgetting and indicate potential new treatment avenues for memory-related disorders. • Depotentiation weakens engram synapses to disrupt memory expression • Engram-specific depotentiation supports active forgetting mechanisms • Neuromodulators and prior activity constrain depotentiation efficacy • Improved understanding of depotentiation may indicate new treatments for memory disorders