# Persistent Pre- and Post-Synaptic Changes After Moderate Traumatic Brain Injury and Mitigation with MitoQ

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2023 · —

## Abstract

TBI was named the signature injury among military personnel served in the recent conflicts in Afghanistan and
Iraq with more than 470,000 confirmed cases of TBI from 2010- 2020. In addition, more than
82,468 Veterans who use VA for their health care have been diagnosed with at least one TBI. Chronic synapse
alternations represent an underappreciated area of interest in TBI pathobiology, with only a few published studies
in the literature (1),(2),(3),(4) and even less examined in in the subacute/chronic phase of TBI. Our preliminary
data show that there are in face persistent pre-synaptic and post-synaptic zone structural and functional
vulnerability following moderate TBI in mice. These long-term changes could hinder synaptic adaptive
mechanisms of the brain (synaptoplasticity) and therefore negatively affect brain recovery following TBI. We
have evidence that presynaptic and post-synaptic protein and lipid components are especially vulnerable
oxidative modifications and proteolysis, then leading to their down regulation. These synaptic changes, if
persisted, could hinder synaptic adaptive mechanisms of the brain (synaptoplasticity) and therefore negatively
affect brain recovery following TBI. Hypothesis: (i) TBI can cause sustained down-regulation of protein
complexes at the pre-synaptic terminal active zone, which are associated with diminished vesicular
neurotransmitter release function. (ii) In parallel, TBI also can cause oxidative and proteolytic damage of key
protein components of the post-synaptic density (PSD) - PDZ-domain scaffold proteins (PSD93, PSD95,
gephyrin) and associated calmodulin-regulator neurogranin, which can lead to instability & reduction of
postsynaptic membrane-bound ionotropic glutamate receptor (NR2A, NR2B GluR1, GluR2), GABA receptor-A
/B and dopamine receptors (D1, D2) and thus compromising the post-synaptic neurotransmission capacity. (iii)
Studying TBI–induced pre- and post-synaptic protein alternations and dysfunctions can be facilitated by the use
of synaptosome preparations isolated from injured mouse brain regions following moderate controlled cortical
impact (CCI) and repeated close head injury (rCHI) are ideally suited to examine pre- and postsynaptic protein
complex as well as in vesicular neurotransmitter release function and post-synaptic glutamate and dopamine
receptor capacity. (iv) novel therapy with an oral mitochondria-targeting BBB-crossing antioxidant Mitoquinone
(MitoQ) can help reduce post-TBI presynaptic and postsynaptic alterations and improve chronic neurobehavioral
functions as supported by our pilot studies.
In this proposal, we first aim to (1) study chronic post- CCI and post-rCHI alterations of key pre-synaptic and
post-synaptic modulatory proteins in synaptosome/synaptoneurosome preparations and by
immunohistochemical (IHC) staining and Immuno-electron microscopy. We then (2) examine chronic pre-
synaptic vesicular neurotransmitter release capacity and post-synaptic glutamate receptors f...

## Key facts

- **NIH application ID:** 10643137
- **Project number:** 1I01RX003832-01A2
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** KEVIN Ka Wang WANG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10643137

## Citation

> US National Institutes of Health, RePORTER application 10643137, Persistent Pre- and Post-Synaptic Changes After Moderate Traumatic Brain Injury and Mitigation with MitoQ (1I01RX003832-01A2). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10643137. Licensed CC0.

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