Nanoscale Scaffolding Domains within the Postsynaptic Density Concentrate Synaptic AMPA Receptors

• Published in: Neuron (Cambridge, Mass.) Mass.), 2013-05, Vol.78 (4), p.615-622
• Main Authors: MacGillavry, Harold D., Song, Yu, Raghavachari, Sridhar, Blanpied, Thomas A.
• Format: Article
• Language: English
• Subjects: Animals; Cytoskeleton; Disks Large Homolog 4 Protein; Excitatory Postsynaptic Potentials - physiology; Hippocampus - cytology; Intracellular Signaling Peptides and Proteins - physiology; Membrane Proteins - physiology; Microscopy; Microscopy, Fluorescence - methods; Nanostructures; Neurons; Neurons - cytology; Neurons - metabolism; Post-Synaptic Density - physiology; Rats; Receptors, AMPA - metabolism; Synaptic Transmission - physiology
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2013.03.009

Scaffolding molecules at the postsynaptic membrane form the foundation of excitatory synaptic transmission by establishing the architecture of the postsynaptic density (PSD), but the small size of the synapse has precluded measurement of PSD organization in live cells. We measured the internal structure of the PSD in live neurons at approximately 25 nm resolution using photoactivated localization microscopy (PALM). We found that four major PSD scaffold proteins were each organized in distinctive ∼80 nm ensembles able to undergo striking changes over time. Bidirectional PALM and single-molecule immunolabeling showed that dense nanodomains of PSD-95 were preferentially enriched in AMPA receptors more than NMDA receptors. Chronic suppression of activity triggered changes in PSD interior architecture that may help amplify synaptic plasticity. The observed clustered architecture of the PSD controlled the amplitude and variance of simulated postsynaptic currents, suggesting several ways in which PSD interior organization may regulate the strength and plasticity of neurotransmission. •Live-cell PALM reveals dynamic patterns of synaptic scaffold distribution in PSDs•Scaffold molecules concentrate in subsynaptic clusters; these are enriched in AMPARs•Activity suppression alters the PSD interior, potentially amplifying plasticity•Clustered architecture shapes amplitude and variance of postsynaptic currents MacGillavry et al. use single-molecule imaging to map protein distribution within live PSDs. Scaffold molecules concentrated in dynamic, subsynaptic clusters enriched in AMPARs. This unforeseen organization shapes amplitude and variance of EPSCs, suggesting new means of regulating neurotransmission.