SYNAPSE TYPE–DEPENDENT TRANS-SYNAPTIC NANOSTRUCTURES COORDINATE RECEPTOR NANODOMAINS WITH PRESYNAPTIC RELEASE SITES IN THE HIPPOCAMPUS

Synaptic transmission efficiency varies depending on specific combinations of presynaptic and postsynaptic cell types, implying that the nanoscale arrangement of presynaptic release machinery and postsynaptic receptors is regulated in a synapse-type–specific manner. In this study, we investigated how synaptic nanostructures formed by presynaptic active zone (AZ) and postsynaptic density (PSD) proteins support such specialization at glutamatergic synapses in the hippocampus. Using quantitative immunofluorescence and multi-color super-resolution microscopy, we measured the molecular composition and nanoscale distribution of endogenous AZ and PSD proteins across multiple synapse types in the rat hippocampal CA3 region. We found that glutamatergic synapses on two interneuron types—TARPγ2-positive synapses on parvalbumin (PV)-expressing interneurons and Elfn1-positive synapses on somatostatin (SOM)-expressing interneurons—contained markedly higher levels of SAPAP/GKAP within the PSD, whereas SynGAP was present at very low abundance, compared with neighboring CA3–CA3 synapses. At TARPγ2-positive synapses, SAPAP was organized into peripheral nanodomains surrounding central Homer1 clusters, and AMPA-type glutamate receptors were selectively enriched along these SAPAP nanostructures. Moreover, Munc13-marked presynaptic release sites were tightly aligned with SAPAP nanodomains at TARPγ2-positive synapses, whereas this AZ–PSD alignment was weaker at Elfn1-positive synapses and CA3–CA3 synapses. Together, these results demonstrate synapse-type–specific differences in AZ–PSD nanoscale organization and suggest that SAPAP-based PSD nanostructures may provide a structural basis that functionally couples AMPA receptor nanodomains to presynaptic release sites in a cell-type–dependent manner.