Hypothesis

Core idea: Excess ribosomal proteins in aged synapses boost local translation of specific postsynaptic proteins that become heavily ubiquitinated, which slows the disassembly of synaptic protein complexes and creates a rigid, over‑consolidated network.

Mechanistic steps:

1. Aging associated drop in ribosomal mRNA but rise in ribosomal proteins (see [1]) raises the translational capacity at synapses.
2. This surplus favors synthesis of proteins with lysine‑rich motifs that are substrates for synaptic ubiquitin ligases (e.g., PSD‑95, GluA2).
3. Concomitant decrease in acetylation and increase in ubiquitination (see [2]) marks these newly made proteins for stable incorporation into complexes rather than rapid turnover.
4. Stable complexes reduce the residence‑time variability of synaptic scaffolds, lowering the effective dissociation rate constants and increasing network modularity.
5. The resulting decrease in dynamic range limits surprise‑driven plasticity, manifesting as slower processing and pattern entrenchment.

Testable predictions:

• In young mouse hippocampus, inhibiting ribosomal protein accumulation (e.g., via siRNA against Rpl10a) will lower the local synthesis rate of ubiquitin‑targeted postsynaptic proteins and increase complex turnover measured by FRAP or single‑molecule tracking.
• Conversely, overexpressing a ribosomal protein in young synapses will recapitulate the aged ubiquitination pattern and reduce complex mobility.
• In aged mice, pharmacological reduction of synaptic ubiquitination (using a selective E3 ligase inhibitor) should rescue complex dissociation rates and improve performance on a reversal‑learning task without altering total protein levels.
• Centenarian‑derived human cortical synapses (see [3]) will show ribosomal protein levels comparable to young tissue and lower ubiquitin‑ligase activity, correlating with higher complex turnover.

Falsification: If manipulating ribosomal protein abundance or synaptic ubiquitination fails to alter complex dissociation rates or cognitive flexibility in either direction, the over‑consolidation model would be unsupported.

Broader implication: Interventions that reintroduce controlled translational noise or ubiquitination dynamics—rather than globally boosting synthesis—may restore synaptic flexibility in aging brains.