Sequential replacement of PSD95 subunits in postsynaptic supercomplexes is slowest in the cortex

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Francis Crick's 1984 hypothesis proposed sequential subunit replacement in dimeric protein complexes to maintain long-term memory despite short protein lifespans.
• It remains unclear if memory-mediating protein complexes undergo sequential subunit replacement in the brain and if this relates to protein lifetime.

Purpose of the Study:

• To investigate the sequential replacement of subunits in postsynaptic density protein 95 (PSD95) supercomplexes in the brain.
• To determine if this replacement process is linked to protein lifetime and memory storage.

Main Methods:

• Utilized single-molecule detection, super-resolution microscopy, and MINFLUX imaging.
• Employed mice with genetically encoded HaloTags, eGFP, and mEoS2 for time-stamping PSD95 subunits in vivo.
• Analyzed PSD95 supercomplexes in different brain regions.

Main Results:

• Identified PSD95-containing supercomplexes with a predominant 12.7 nm separation, indicating dimeric composition.
• Demonstrated sequential replacement of individual PSD95 subunits over days to weeks.
• Observed the slowest subunit replacement in the cortex, correlating with the longest PSD95 protein lifetime.

Conclusions:

• Protein supercomplexes in the postsynaptic density are maintained by gradual subunit replacement, ensuring organizational stability.
• Extended Crick's model: synapses with slow subunit replacement and long protein lifetimes are specialized for long-term memory storage.
• These specialized synapses are enriched in cortical superficial layers, where long-term memories are consolidated.