Hypometabolism induces silent memory engrams via hyperpolarization-disrupted replay-mediated consolidation

Silent memory engrams---neuronal ensembles storing memories inaccessible to natural cues yet amenable to artificial stimulation---underlie retrieval deficits in models of retrograde amnesia and Alzheimer's disease (AD). Although current models of silent engram formation focus on synaptic plasticity impairments, including protein synthesis inhibition, they overlook upstream hypometabolism's role in disorders featuring amnesia-like memory impairments. Here, using a biophysically detailed computational model of the entorhinal-hippocampal-amygdalar network coupled with cellular energy dynamics, we demonstrate that lowering intracellular adenosine triphosphate (ATP) levels activates ATP-sensitive potassium (K _ATP ) channels, inducing hyperpolarization that spares encoding of contextual fear engrams but selectively suppresses offline replays critical for consolidation. Consequently, basolateral amygdala fear neurons evade natural cue-evoked recall yet respond to optogenetic-like synchronous dentate gyrus activation, thus forming silent engrams independent of synaptic plasticity impairments. Our model uncovers a metabolic pathway to silent engrams, suggesting that hypometabolic disorders exhibiting reduced offline replays and amnesia-like impairments---including Alzheimer's disease, traumatic brain injury, hypoxic-ischemic encephalopathy, and depression---may share this pathway. Therapeutically, targeted blockade of K _ATP -mediated hyperpolarization could restore replay dynamics and natural recall, positioning K _ATP channels as a tractable target for precision medicine in hypometabolic amnestic disorders.