Aging-related cellular and molecular changes reveal a role for Bglap3+ neurons in MEC spatial cognition

Abstract Aging-related cognitive decline, including impairments in spatial orientation and memory, has been linked to dysfunction within the hippocampus and medial entorhinal cortex (MEC). However, the cellular and molecular alterations underlying MEC aging remain poorly understood. Here we show that old mice exhibit a reduced proportion of grid cells and decreased spatial stability. Transcriptomic profiling of the MEC using 10x Genomics Visium technology reveals 1664 differentially expressed genes between young and old mice. Among these, Bglap3 is identified as a marker gene for a subpopulation of Layer III neurons that showed an age-associated reduction in cell number. Chemogenetic silencing of Bglap3 + neurons in young mice impairs spatial tuning of MEC neurons. Together, these findings elucidate cellular and molecular mechanisms contributing to age-related MEC dysfunction and suggest that the loss of Bglap3 + neurons may underlie spatial coding deficits in aging.