From Mechanical Perturbation to Pathological Locking: Temporal-Mechanical Evolution of the Postsynaptic Density After Traumatic Brain Injury.

Authors

Yibin Jia, Zixuan Cao, Hanjiang Xue, Zhebin Feng, Zhiguo Ma, Zhicheng Tian, Xin Li, Peng Luo

Published in

CNS neuroscience & therapeutics. Volume 32. Issue 11.

Abstract

Traumatic brain injury (TBI) induces persistent cognitive deficits, yet conventional biochemical and structural models often fail to explain synaptic signal collapse in the absence of overt tissue rupture.
Here, we present a hypothesis-generating mechanobiological framework that positions postsynaptic density (PSD)-a multivalent protein condensate governed by liquid-liquid phase separation (LLPS)-as a primary locus of synaptic mechanovulnerability. We argue that TBI-induced synaptic pathology is not merely a quantitative loss of molecular components, but a progressive, staged material state transition of the PSD network. This pathological evolution initiates with hyperacute mechanical deconstruction, leading to physical scaffold decoupling and nanoscale receptor misalignment. It then advances through an acute mechano-metabolic crisis characterized by enzymatic scaffold cleavage and impaired re-condensation, ultimately culminating in a chronically locked, low-dynamic "solidified" state. Furthermore, post-injury extracellular matrix stiffening and the mechanical exposure of cryptic epitopes trigger aberrant microglial pruning via mechanosensors such as Piezo1, permanently dismantling neural circuits. Because the supporting evidence is heterogeneous, we explicitly grade each element of this model as established directly in TBI, supported in non-TBI synaptic systems, extrapolated from reconstituted condensates, or hypothetical.
By bridging macroscopic biomechanics with nanoscale molecular pathology, this review highlights a critical conceptual gap and proposes "mechano-therapeutics" as a hypothesis-generating concept rather than an established treatment avenue. We suggest that strategies targeting the physical properties of the synapse, such as stabilizing scaffold oligomerization, modulating mechanotransduction pathways, and restoring physiological tissue stiffness, are candidate directions whose feasibility, delivery, cell-type specificity, timing, and safety must first be established in preclinical models before any clinical translation to rescue synaptic homeostasis and cognitive function after TBI.

PMID:
42992633
Bibliographic data and abstract were imported from PubMed on 06 Nov 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.