Molecular mechanisms mediating engram ensemble retrievability state in mice

Engrams, ensembles of neurons that store memories, exist along a continuum of retrievability. Normally, sensory cues can reactivate a latent engram to trigger recall; however, in a silent engram, only direct optogenetic activation, not sensory cues, induces memory retrieval. Here, we investigated the molecular mechanisms that govern engram silencing and un-silencing using forgetful TgCRND8 (Tg) mice, which show enhanced endocytosis of GluA2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Although Tg mice form fear memories, they fail to retrieve them, consistent with engram silencing. Blocking GluA2 endocytosis during engram activation (training, retrieval attempts, or optogenetic stimulation) increased synaptic GluA2 content in engram neurons and restored memory retrieval, effectively un-silencing the engram. Similarly, in wild-type mice, post-training long-term depression (LTD)-type stimulation of engram neurons induced silent engrams that could be un-silenced by disrupting GluA2 removal. Together, these findings identify GluA2 trafficking as a key regulator of engram retrievability and point to potential strategies for restoring inaccessible memories.