Abstract

Neurocognitive consequences of blast-induced traumatic brain injury (bTBI) pose significant concerns for military service members and veterans with the majority of "invisible injury." However, the underlying mechanism of such mild bTBI by low-intensity blast (LIB) exposure for long-term cognitive and mental deficits remains elusive. Our previous studies have shown that mice exposed to LIB result in nanoscale ultrastructural abnormalities in the absence of gross or apparent cellular damage in the brain. Here we tested the hypothesis that glutamatergic hyperexcitability may contribute to long-term learning deficits. Using brain slice electrophysiological recordings, we found an increase in averaged frequencies with a burst pattern of miniature excitatory postsynaptic currents (mEPSCs) in hippocampal CA3 neurons in LIB-exposed mice at 1- and 7-days post injury, which was blocked by a specific NMDA receptor antagonist AP5. In addition, cognitive function assessed at 3-months post LIB exposure by automated home-cage monitoring showed deficits in dynamic patterns of discrimination learning and cognitive flexibility in LIB-exposed mice. Collected hippocampal tissue was further processed for quantitative global-proteomic analysis. Advanced data-independent acquisition for quantitative tandem mass spectrometry analysis identified altered expression of proteins involved in synaptic plasticity and serine protease inhibitors in LIB-exposed mice. Some were correlated with the ability of discrimination learning and cognitive flexibility. These findings show that acute glutamatergic hyperexcitability in the hippocampus induced by LIB may contribute to long-term cognitive dysfunction and protein alterations. Studies using this military-relevant mouse model of mild bTBI provide valuable insights into developing a potential therapeutic strategy to ameliorate hyperexcitability-modulated LIB injuries.

Department(s)

Mining Engineering

Comments

This publication was made possible in part by funding from the Department of Veterans Affairs Offices of Research & Development (VA ORD) the LAMb/ShEEP programs, the BLR&D Director Service program (UFR-002-18F), Open-Field Blast (OFB) Core, and the Collaborative Merit Review for TBI Research Program (I01 BX004313-01A1); as well as the DoD Congressionally Directed Medical Research Programs (CDMRP) for the Peer Reviewed Alzheimer’s Research Program Convergence Science Research Award (PRARP-CSRA; AZ180043) and the research funds of the University of Missouri (ZG); as well as by funding from NIH National Heart, Lung, and Blood Institute (R01 HL142133, R01 HL139523, and R01 HL159157 grants to DL).

Keywords and Phrases

Chronic cognitive dysfunction; Glutamatergic hyperexcitability; Home-cage monitoring; Label-free proteomic quantitation; Primary open-field blast

International Standard Serial Number (ISSN)

1095-953X; 0969-9961

Document Type

Article - Journal

Document Version

Final Version

File Type

text

Language(s)

English

Rights

© 2022 Elsevier, All rights reserved.

Creative Commons Licensing

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Publication Date

01 Apr 2022

PubMed ID

35077822

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