Age-Related Changes in Density, Arborization and Expression of NMDA Receptors of Somatostatin Martinotti Neurons in the Mouse mPFC

Aging is associated with progressive alterations in cortical circuits that compromise cognitive function. Somatostatin-positive (SST+) Martinotti interneurons, which regulate pyramidal cell activity in the medial prefrontal cortex (mPFC), are particularly relevant for inhibitory control, yet their age-related vulnerability remains poorly understood. Here, we examined SST+ Martinotti cells in mice at 3, 9, and 16 months of age, focusing on neuronal density, dendritic arborization, and expression of NMDA receptor subunits GluN1 and GluN2B. Our findings reveal a significant decline in SST+ cell density in aged male mice, whereas female mice displayed an increase in dendritic arborization with age. Analysis of NMDA receptor puncta showed a reduction in GluN1 density and puncta size in older animals, particularly in females. In contrast, GluN2B puncta density decreased in both sexes, while puncta size increased, suggesting greater clustering with aging. These results indicate that SST+ Martinotti cells undergo structural and molecular remodeling in a sex-dependent manner, which may disturb excitatory-inhibitory balance in the mPFC. Such alterations could underlie age-related deficits in prefrontal function and highlight SST+ interneurons as critical targets of cortical aging.