GluA1-containing AMPA receptors are necessary for sparse memory engram formation

Memory formation depends on the selective recruitment of neuronal ensembles into circuits known as engrams, which represent the physical substrate of memory. Sparse encoding of these ensembles is essential for memory specificity and efficiency. AMPA receptor (AMPAR) subunits, particularly GluA1, play a central role in synaptic plasticity, which underpins memory encoding. This study investigates how GluA1 expression influences the recruitment of neurons into memory engrams. Using global GluA1 knockout (GluA1^KO) mice, localized knockout models, and contextual fear-conditioning paradigms, we evaluated the role of GluA1 in memory formation and engram sparsity. GluA1^KO mice exhibited impaired short-term memory retention but preserved 24-hour contextual memory. Despite this, these mice displayed increased expression of the immediate early gene Arc in hippocampal neurons, indicative of a denser engram network. Electrophysiological analyses revealed reduced synaptic strength in GluA1-deficient neurons, irrespective of Arc expression. Localized GluA1 knockout in the hippocampus confirmed that GluA1 deficiency increases neuronal recruitment into engrams, disrupting the sparse encoding typically observed in wild-type mice. These findings demonstrate that GluA1-containing AMPARs constrain engram size, ensuring selective recruitment of neurons for efficient memory encoding. By regulating synaptic plasticity, GluA1 facilitates both the encoding and size of memory circuits. This study highlights the critical role of GluA1 in maintaining sparse engram formation and provides insight into mechanisms underlying memory deficits in conditions where synaptic composition is altered.