Spatial Coding Dysfunction & Network Instability in the Aging Medial Entorhinal Cortex

Across species, spatial memory declines with age, possibly reflecting altered hippocampal and medial entorhinal cortex (MEC) function. However, the integrity of cellular and network-level spatial coding in aged MEC is unknown. Here, we leveraged electrophysiology to assess MEC function in young, middle-aged, and aged mice navigating virtual environments. In aged grid cells, we observed impaired stabilization of context-specific spatial firing, correlated with spatial memory deficits. Additionally, aged grid networks shifted firing patterns often but with poor alignment to context changes. Aged spatial firing was also unstable in an unchanging environment. In these same mice, we identified 462 genes differentially expressed with age in MEC, 61 of which had expression correlated with spatial firing stability. These genes were interneuron-specific and related to synaptic transmission. Together, these findings identify coordinated transcriptomic, cellular, and network changes in MEC implicated in impaired spatial memory in aging. Overall design: Neuronal nuclei were isolated from subdissected MECs to compare transcriptomes of young, mature, and aged mice with electrophysiological recordings.