Synaptic Organization of Surface AMPARs Changes by Brain Region and Tauopathy

Abstract

The distribution of synaptic and extra-synaptic AMPA receptors (AMPARs) on neuronal plasma membranes is correlated with learning and memory. Although AMPAR organization has been extensively studied in neuronal cultures, its native cell-surface distribution in intact adult brain tissue across distinct brain regions and in neurodegenerative pathology remains poorly understood. Here, we combine a selective small-molecule labeling strategy with two-color 3D super-resolution dSTORM imaging to map native surface AMPAR organization at the nanoscale in 30 micron thick mouse brain slices. We find that wild-type mice exhibit marked regional differences in AMPAR organization, with the CA1 hippocampus containing a substantially larger extrasynaptic AMPAR pool than the nearby motor and somatosensory cortex. In the PS19 tauopathy mouse model, at an age preceding overt neurodegeneration, AMPAR organization is selectively disrupted in the hippocampus but largely preserved in the cortex. Specifically, we observe depletion of the extrasynaptic receptor pool together with reduced synaptic nanodomain organization, revealing early molecular-scale synaptic remodeling associated with tau pathology. These findings provide direct structural insight into region- and disease-dependent AMPAR organization in intact adult brain tissue and establish a broadly applicable framework for nanoscale investigation of synaptic receptor architecture in health and neurological disease.