Excessive inhibition in the medial prefrontal cortex contributes to cognitive susceptibility in aging

Aging is the most impactful risk factor for cognitive decline. The prefrontal cortex (PFC), a brain region essential for higher-order cognition, undergoes age-related synaptic alterations which are postulated to yield an excitation/inhibition imbalance within the PFC. Here, we assessed cognitive performance in young and aged mice using a battery of behavioral tests linked to PFC function. Behavioral variability within the aged cohort suggested structured heterogeneity in cognitive performance. Using a data-driven analytical framework integrating behavioral dimensionality reduction, consensus clustering, and spectral embedding we achieved robust and stable behavioral subgroup separation within the aged population. This approach revealed a subset of "cognitively susceptible" aged mice with pronounced memory and novelty-directed exploration deficits, distinct from both "resilient" aged mice and young controls. Unlike resilient aged mice, susceptible mice showed intact social preference. Susceptible aged mice exhibited elevated levels of the inhibitory synaptic proteins Gephyrin and VGAT in the PFC, a pattern absent in resilient aged mice. Notably, the increase in Gephyrin was accounted for by a higher density of inhibitory synapses, indicating a structural shift toward inhibition. Consistent with this mechanism, optogenetically enhancing inhibition in the PFC of young mice was sufficient to recapitulate the memory and novelty-exploration deficits observed in susceptible aged mice. Altogether, these findings implicate excessive prefrontal inhibition as a mechanistic substrate contributing to cognitive susceptibility in unsuccessful aging.