Title

Multi-Focal Neuronal Ultrastructural Abnormalities and Synaptic Alterations in Mice after Low-Intensity Blast Exposure

Abstract

Service members during military actions or combat training are exposed frequently to primary blast generated by explosive weaponry. The majority of military-related neurotrauma are classified as mild and designated as "invisible injuries" that are prevalent during current conflicts. While the previous experimental blast injury studies using moderate- to high-intensity exposures focused mainly on gross and microscopic neuropathology, our previous studies have shown that low-intensity blast (LIB) exposures resulted in nanoscale subcellular myelin and mitochondrial damages and subsequent behavioral disorders in the absence of gross or detectable cellular damage. In this study, we used transmission electron microscopy to delineate the LIB effects at the ultrastructural level specifically focusing on the neuron perikaryon, axons, and synapses in the cortex and hippocampus of mice at seven and 30 days post-injury (DPI). We found dysmorphic dark neuronal perikaryon and "cytoplasmic aeration" of dendritic processes, as well as increased microtubular fragmentation of the myelinated axons along with biochemically measured elevated tau/phosphorylated tau/Aß levels. The number of cortical excitatory synapses decreased along with a compensatory increase of the post-synaptic density (PSD) thickness both at seven and 30 DPI, while the amount of hippocampal CA1 synapses increased with the reduced PSD thickness. In addition, we observed a significant increase in protein levels of PSD95 and synaptophysin mainly at seven DPI indicating potential synaptic reorganization. These results demonstrated that a single LIB exposure can lead to ultrastructural brain injury with accompanying multi-focal neuronal organelle alterations. This pre-clinical study provides key insights into disease pathogenesis related to primary blast exposure.

Department(s)

Mining and Nuclear Engineering

Comments

This publication was made possible by funding from the DoD Congressionally Directed Medical Research Programs (CDMRP) for the Peer Reviewed Alzheimer's Research Program Convergence Science Research Award (PRARP-CSRA; AZ140109). We also appreciate the support from the Electron Microscopy Core (EMC) Excellence in Electron Microscopy and EMC Fellowship awards (LK and HS) and the research funds from Department of Pathology and Anatomical Sciences from the University of Missouri School of Medicine (ZG). This study was also supported by the award I21BX002215, I01BX003527 and I21BX003807 from the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development and the Cure Alzheimer's Fund (WX).

Keywords and Phrases

Axonal Microtubule Injury; Low-Intensity Open-Field Blast; Synaptic Alterations; Tau; Transmission Electron Microscopy

International Standard Serial Number (ISSN)

0897-7151; 1557-9042

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2019 Mary Ann Liebert Inc., All rights reserved.

Publication Date

01 Jul 2019

PubMed ID

30667346

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