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Updated: Jun 14, 2025

Assessing Changes in Synaptic Plasticity Using an Awake Closed-Head Injury Model of Mild Traumatic Brain Injury
09:49

Assessing Changes in Synaptic Plasticity Using an Awake Closed-Head Injury Model of Mild Traumatic Brain Injury

Published on: January 20, 2023

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Cognitive dysfunction following brain trauma results from sex-specific reactivation of the developmental pruning

Dena Arizanovska, Carlos A Dallera, Oluwarotimi O Folorunso

    Biorxiv : the Preprint Server for Biology
    |August 30, 2024
    PubMed

    Insights

    Severe brain trauma causes cognitive loss via synaptic damage. This damage, driven by D-serine and NMDARs, is reversible and offers a neuroprotective strategy for brain injury patients.

    Area of Science:

    • Neuroscience
    • Traumatic Brain Injury Research
    • Synaptic Plasticity

    Background:

    • Cognitive deficits after brain trauma are linked to focal damage, with limited success in clinical trials targeting perilesional tissue.
    • Previous research focused on cellular changes near the injury site, overlooking broader synaptic alterations.

    Purpose of the Study:

    • To investigate the mechanisms of expansive synaptic damage beyond the focal injury site in a mouse brain injury model.
    • To identify key molecular players and pathways contributing to progressive synaptic loss after brain trauma.
    • To explore the potential for therapeutic intervention by targeting identified mechanisms.

    Main Methods:

    • Utilized a mouse model of severe brain injury to induce and study synaptic damage.
    • Analyzed the role of D-serine release from activated microglia and astrocytes.
    • Investigated the involvement of N-methyl-D-aspartate receptors (NMDARs) and complement-mediated synaptic tagging.
    • Examined the reactivation of developmental synaptic pruning processes.
    • Assessed the reversibility of the synaptic damage pathway.
    • Analyzed human brain tissue from acute brain injury patients.

    Main Results:

    • Demonstrated that brain injury causes synaptic damage in regions outside the focal lesion.
    • Identified prolonged D-serine release from microglia and astrocytes as a driver of synaptic damage.
    • Showed that this leads to NMDAR hyperactivation, complement-mediated synapse tagging, and aberrant pruning.
    • Confirmed that this pathological pathway is reversible at multiple stages.
    • Found these mechanisms present in human brain tissue from patients with brain injuries.

    Conclusions:

    • Synaptic damage following brain trauma is a progressive process driven by D-serine/NMDAR overactivation and aberrant pruning.
    • The identified mechanistic pathway is reversible, presenting a potential therapeutic target.
    • Findings in human brain tissue support a neuroprotective strategy for treating brain injury.

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