Age-related synaptic signatures of brain and cognitive reserve in the rat hippocampus and parahippocampal regions

Age-related cognitive decline varies widely among individuals, with some showing resilience despite older age. This study examines synaptic markers of glutamatergic and GABAergic neurotransmission in the hippocampus and cortex of older rats with differing cognitive abilities, aiming to uncover mechanisms that contribute to cognitive resilience. We observed significant age-related reductions in vesicular glutamate transporter VGluT1, particularly in the stratum oriens (SO), radiatum (SR), and lacunosum-moleculare (SLM) of the dorsal CA3 and SLM of the dorsal CA1. Furthermore, loss of VGluT1 in the dorsal CA3-SLM correlated with severity of memory impairment. Higher levels of the vesicular GABA transporter (VGAT) were associated with better spatial learning in older rats, across several synaptic zones of the dorsal hippocampus, including the outer molecular layer of the dentate gyrus (DG), and the SO, SR, SLM, and pyramidal cell layers of both CA3 and CA1. This suggests that enhanced inhibitory neurotransmission specific to the dorsal aspect of the hippocampus may protect against age-related cognitive decline. While the dorsal hippocampus showed consistent age- and memory-related changes, markers in the ventral hippocampus remained largely intact. In the perirhinal cortex, VGluT1 declined with no changes in VGAT, while both markers remained unchanged in other cortical regions, including the lateral entorhinal, retrosplenial, and posterior parietal cortices. These findings highlight region-specific patterns of synaptic aging as potential markers of brain and cognitive reserve.