SPECIALISED CA1 NEURONAL SUBTYPES DIFFERENTIALLY SUPPORT MEMORY ENCODING AND RETRIEVAL

Prevailing models of hippocampal memory posit largely homogeneous CA1 neuronal ensembles that support both encoding and recall, leaving open the question of whether cellular specialization underlies these distinct processes. Here, we identify two molecularly and structurally distinct subtypes of CA1 pyramidal neurons that share similar intrinsic electrophysiological properties yet serve separable roles in memory encoding and retrieval. Using genetic proxy labelling based on CaMKIIα promoter activity, we distinguish neurons with high CaMKIIα expression (Type A) from a previously unappreciated population with low CaMKIIα promoter activity (Type B). Comprehensive morphological, molecular, and functional analyses reveal marked differences between these subtypes. Type A neurons exhibit lower baseline intracellular calcium, reduced dendritic complexity, and a transcriptomic profile enriched for pathways associated with cytoskeletal remodelling. In contrast, Type B neurons display higher baseline calcium levels, elevated population-level baseline activity, and gene expression signatures consistent with enhanced synaptic transmission. During contextual fear conditioning, both neuronal subtypes are recruited during fear encoding; however, during recall, activity is selectively maintained in the
Type A neuronal subpopulation. Chemogenetic silencing further demonstrated that while Type B neurons were indispensable for memory encoding, Type A neurons were essential for memory recall. Together, these findings reveal a division of labour within CA1, in which neurons with a transcriptional and functional profile poised for rapid synaptic engagement support encoding. In contrast, neurons primed for structural remodelling sustain memory retrieval. This framework redefines the engram as a dynamic assembly of specialized neuronal subtypes that differentially support distinct phases of memory.