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

Author:

Morris Katie1,Bulovaite Edita2,Kaizuka Takeshi2,Schnorrenberg Sebastian3,Adams Candace14,Komiyama Noboru H256,Mendive-Tapia Lorena47,Grant Seth GN25,Horrocks Mathew H14

Affiliation:

1. EaStCHEM School of Chemistry, University of Edinburgh

2. Genes to Cognition Program, Centre for Clinical Brain Sciences, University of Edinburgh

3. EMBL Imaging Centre, European Molecular Biology Laboratory

4. IRR Chemistry Hub, Institute for Regeneration and Repair, University of Edinburgh

5. Simons Initiative for the Developing Brain (SIDB), Centre for Discovery Brain Sciences, University of Edinburgh

6. The Patrick Wild Centre for Research into Autism, Fragile X Syndrome & Intellectual Disabilities, Centre for Discovery Brain Sciences, University of Edinburgh

7. Centre for Inflammation Research, University of Edinburgh

Abstract

The concept that dimeric protein complexes in synapses can sequentially replace their subunits has been a cornerstone of Francis Crick’s 1984 hypothesis, explaining how long-term memories could be maintained in the face of short protein lifetimes. However, it is unknown whether the subunits of protein complexes that mediate memory are sequentially replaced in the brain and if this process is linked to protein lifetime. We address these issues by focusing on supercomplexes assembled by the abundant postsynaptic scaffolding protein PSD95, which plays a crucial role in memory. We used single-molecule detection, super-resolution microscopy and MINFLUX to probe the molecular composition of PSD95 supercomplexes in mice carrying genetically encoded HaloTags, eGFP and mEos2. We found a population of PSD95-containing supercomplexes comprised of two copies of PSD95, with a dominant 12.7 nm separation. Time-stamping of PSD95 subunits in vivo revealed that each PSD95 subunit was sequentially replaced over days and weeks. Comparison of brain regions showed subunit replacement was slowest in the cortex, where PSD95 protein lifetime is longest. Our findings reveal that protein supercomplexes within the postsynaptic density can be maintained by gradual replacement of individual subunits providing a mechanism for stable maintenance of their organization. Moreover, we extend Crick’s model by suggesting that synapses with slow subunit replacement of protein supercomplexes and long protein lifetimes are specialized for long-term memory storage and that these synapses are highly enriched in superficial layers of the cortex where long-term memories are stored.

Publisher

eLife Sciences Publications, Ltd

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