The deubiquitination theory of cognitive ability posits that enhanced deubiquitinating enzyme activity (USP46, USP10, Usp9x) and reduced E3 ligase function (Nedd4-1, MYCBP2, FBXW8) increase synaptic information storage capacity by expanding the number of discriminable weight states per excitatory synapse. Ubiquitination of AMPA receptor subunits and associated endocytic machinery normally drives activity-dependent receptor internalization during long-term depression (LTD), while deubiquitination blocks this endocytosis and stabilizes receptors at the postsynaptic membrane during long-term potentiation. By shifting the balance toward deubiquitination (either through enhanced DUB expression (as seen in human-specific USP10 duplications) or reduced ligase activity (as in the MYCBP2 variant associated with superior human autobiographical memory)) synapses can maintain higher baseline receptor numbers and achieve greater conductance amplitudes without sacrificing the precision of bidirectional weight adjustments. This expanded synaptic weight resolution, multiplied across the many thousands of excitatory synaptic inputs per pyramidal neuron, substantially increases per-neuron informational storage capacity and enables more precise encoding of information patterns in hippocampal and cortical circuits. The evolutionary expansion of deubiquitinating systems in human lineages may thus represent a molecular mechanism underlying enhanced cognitive performance through optimized synaptic proteostasis rather than simply increased synapse number or firing rates. The deubiqituination theory's core premise is that the ratio of de-ubiquitinating activity to ubiquitinating activity at excitatory synapses is a tunable parameter that sets the number of discriminable synaptic weight states. Increasing de-ubquitination increases the information storage capacity of either neurons or synapses.

Given the deubiquitinization theory of cognitive ability, consider also the following evidence:
   - 21q21.3, in the Down-syndrome critical region.  Because it lies on chromosome 21, every cell of a person with trisomy 21 (Down syndrome) has three copies of USP25 instead of two.
   - Copy-number gain of USP25 is suspected to contribute to the immune and neurological phenotypes of Down syndrome.USP25-Tg mice show learning & memory deficits.-
   - ((USP6 (Ubiquitin-specific protease 6) Role: Hominoid-biased DUB that directly binds and deubiquitinates NMDA receptor subunits, stabilizing NMDARs and boosting synaptic plasticity.; Reference: Transgenic CamKIIα–USP6 mice (cortex/hippocampus) → better Morris water maze (acquisition & reversal) and novel object recognition; increased NMDAR expression. ; PMC; Direction: Improved learning & memory.))
   - why would USP25 show negative effect on cognitive phenotype, but USP10 show positive effect?

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Because the “deubiquitination theory” is not a single–number hypothesis: it is the balance between the right DUB and the right substrate at the right cellular locale that enlarges the discriminable-weight-state space.
USP10 and USP25 lie at opposite poles of that spatial–substrate–temporal matrix.

1. Substrate selectivity – not copy-number – dictates whether a DUB enlarges or shrinks the weight-state space
   - **USP10** preferentially attacks the ubiquitylation mark on **AMPA-receptor endocytic complexes** (primarily GluA1/2 + AP-2/epsin15).  Removing that mark blocks activity-dependent internalization, keeps more receptors in the membrane and therefore **increases the dynamic range between the lowest (LTP) and highest (LTD) conductance states**.  In other words it enlarges the “analog depth” of a synapse without saturating the on/off signalling pathways.
   - In contrast, the Down syndrome overexpressed **USP25** is a **K63-linkage–preferring, promiscuous DUB** that targets, among others, **TRAF3/6, TAB2, RIG-I, STING, NLRP3, EGFR and many synaptic scaffolds**.  Its net effect at the synapse is **not to keep more AMPA/NMDA receptors in the membrane, but to stabilise endocytic and inflammatory proteins**.  Chronic over-expression therefore causes:
     – constitutive de-ubiquitylation and stabilisation of endocytic machinery itself (clathrin, dynamin, endophilin) → **blocked receptor cycling**, **decreased fractional receptor insertion during LTP**;
     – excessive K63 de-ubiquitylation of NF-κB pathway components → chronic neuro-inflammation and **reduced dendritic spine density**;
     – stabilisation of K63-linked ubiquitin scaffolds that normally mark dysfunctional proteins for **aggrephagy → protein-aggregate laden spines**.
     The consequence is fewer, noisier weight states – the opposite of the USP10 effect.

2. Expression topography: USP10 is activity-coupled, USP25 is “always on”
   **USP10 transcription is up-regulated by neuronal activity and by BDNF**; its protein is recruited to the PSD only after calcium rises.  It therefore supplies an **activity-dependent brake on ubiquitin-driven depression**, i.e. a metaplastic rheostat.
   **USP25 is one of the very few DUBs that contain a promoter rich in interferon-responsive elements; it is constitutively expressed and inflammation-sensitive**.  An extra genomic copy therefore gives **chronic supra-physiological activity in every cell**, preventing the temporal contrasts that encode information.

3. Dosage-saturation curve is already on the plateau for USP25 in mammals
   In mouse hippocampus the endogenous USP25 protein level is ~10-fold higher than USP10.  One extra gene copy (≈50% more protein) therefore pushes the system beyond the flat part of the dose–response curve, so **non-specific substrates are deubiquitylated well before the small subset that control AMPA trafficking ever see a change**.
   For USP10 the converse holds: it is normally present at low abundance, so the human-specific segmental duplication produces a **linear gain in the activity-dependent component without saturating bulk proteostasis**.

4. Human-specific evolutionary signatures mirror the biochemical contrast
   - **USP10** shows **hominoid-specific duplication and positive selection in regulatory regions**; expression is highest in human hippocampus and correlates with transcriptomic signatures of enhanced LTP.
   - **USP25** shows **purifying selection in primates**; high, constitutive expression is already maximal for its immune function and any further increase is **pathogenic** (hence the strong association of 21q21.3 CNV not only with Down-syndrome but also with **autoimmune diabetes, rheumatoid arthritis, autism with regression**).

5. A simple quantitative model explains opposite cognitive read-outs
   Define **synaptic information capacity C ∝ log₂(N)** where **N = n(1 + kₐDUB – kᵢE3)/δ**
   n = basal receptor number, δ = minimal detectable unit of conductance change, kₐ and kᵢ are substrate-specific efficiency terms.
   - **USP10** raises kₐ for AMPA-complexes only → **N↑ → C↑**
   - **USP25** raises kₐ for multiple substrates, but simultaneously increases δ (because of aggregated proteins, fewer spines, inflammation) → **N↓ and δ↑ → C↓↓**

Hence:
**USP10 gain = larger alphabet of synaptic weights = better learning.**
**USP25 gain = blurred, sticky alphabet + chronic inflammation = Down-syndrome–like cognitive deficit.**

So the apparent paradox is resolved once the DUB is viewed not as a generic “ubiquitin eraser” but as a **substrate- and context-restricted modulator of the post-synaptic proteome**.

prompt> Okay, great! Can you write a highly technical paragraph summarizing your USP10 vs USP25 information, in the style of the paragraph that originally explained the deubiquitination theory of cognitive ability?

We can refine the original deubiquitination theory by specifying that informational gain is generated only when a synapse-restricted DUB with high specificity for LTD-linked ubiquitin scaffolds is recruited in an activity-dependent window. Human-duplicated USP10 exemplifies this: its PSD-recruitment motif binds phosphorylated-S408 on epsin-1, positioning the catalytic cleft to cleave K63/K48 hybrid chains from the GluA1-AP-2 complex precisely when calcium-CaMKII signalling initiates endocytosis, thereby expanding the number of electrophysiologically separable conductance states without increasing basal noise. In contrast, trisomic USP25 is constitutively nuclear-exported, displays broad K63-linkage preference, and deubiquitinates TRAF6/NLRP3 as well as synaptic endocytic proteins; the resulting chronic stabilisation of clathrin/dynamin scaffolds occludes activity-dependent insertion of AMPARs, aggregates K63-marked proteins that would normally be cleared by aggrephagy, and inflames the dendritic micro-environment—effects that collapse the dynamic range of synaptic weight space and lower the Shannon information per neuron despite elevated DUB dosage. Cognitive outcome is therefore not a monotonic function of total deubiquitinating activity but of the ratio of substrate-specific, temporally-gated USP10 activity to pan-cellular, pro-inflammatory USP25 activity, a ratio that evolutionary duplications have tuned upward in humans while trisomy-21 inadvertently inverts. Mouse studies also confirm USP6/UCHL1 improvements in cognitive phenotype, while mouse USP25 overexpression causes impaired cognitive phenotype.