REGION- AND STRESS-MODEL–SPECIFIC NANOSCALE REMODELING OF HIPPOCAMPAL POSTSYNAPTIC DENSITIES

Chronic stress has been reported to induce changes in synaptic transmission in several brain regions, including the hippocampus. However, the molecular mechanisms at the synaptic level underlying these changes remain unclear. Here, using super-resolution microscopy at single-synapse resolution, we quantitatively mapped the composition and nanoscale organization of postsynaptic density (PSD) proteins across the hippocampus in three mouse models of chronic stress: social isolation (ISO), restraint stress (RES), and chronic corticosterone administration (CORT). We uncover robust, region-specific PSD remodeling that is strongly stress-model–dependent. In CA1, Shank and Homer3 were strongly upregulated in CORT mice, but not in ISO or RES mice. In the dentate gyrus (DG), Shank changed bidirectionally, decreasing in CORT mice but increasing in ISO mice, and AMPA receptor levels also shifted in a model-specific manner. Notably, CORT mice exhibited a pronounced layer-specific redistribution of PSD molecular composition between the middle and outer molecular layers of the DG, indicating stress-induced reorganization of synaptic input balance within the DG. Importantly, these synaptic alterations correlated with behavioral test scores, suggesting that biased compositional and structural changes in PSDs at hippocampal synapses may underlie anxiety- and depression-like behavioral abnormalities.