Gulf War agent exposure causes impairment of long-term memory formation and neuropathological changes in a mouse model of Gulf War Illness.

Zuchra Zakirova,Jon Reed,Ghania Ait-Ghezala,Fiona Crawford,Laila Abdullah,Venkatarajan Mathura,Gogce Crynen,Myles Mullan,Michael J Mullan,Nadee Nissanka,Miles Tweed,Tiziana Rubino

doi:10.1371/journal.pone.0119579

Zuchra Zakirova, Jon Reed + Show 10 more

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https://doi.org/10.1371/journal.pone.0119579

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Abstract

Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component such as memory deficits, neurological, and musculoskeletal problems. There are ample data that demonstrate that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI post deployment to the Persian GW. In the current study, we examined the consequences of acute (10 days) exposure to PB and PER in C57BL6 mice. Learning and memory tests were performed at 18 days and at 5 months post-exposure. We investigated the relationship between the cognitive phenotype and neuropathological changes at short and long-term time points post-exposure. No cognitive deficits were observed at the short-term time point, and only minor neuropathological changes were detected. However, cognitive deficits emerged at the later time point and were associated with increased astrogliosis and reduction of synaptophysin staining in the hippocampi and cerebral cortices of exposed mice, 5 months post exposure. In summary, our findings in this mouse model of GW agent exposure are consistent with some GWI symptom manifestations, including delayed onset of symptoms and CNS disturbances observed in GWI veterans.

Highlights

At least 26–32% of US and UK military personnel who were deployed to the Persian Gulf in the 1990–91 conflict are currently afflicted with the chronic multi-symptom illness known as Gulf War Illness (GWI) [1,2,3,4,5,6]
Our observations are in accordance with our previous studies and those of others that showed either a lack of or marginal microglial activation [20,34,49], but given the potentially transient nature of microgliosis [53,54,55], it is possible that the time points we examined in our current study flanked a period of microgliosis which had subsided by the 5 month time point
We believe that our model will be instrumental in enabling further research into the biological pathways that are modulated at late time points after GW agent exposure, which is the time point of most relevance to the GWI patient population who received their pathogenic exposures more than 23 years ago

Summary

Introduction

At least 26–32% of US and UK military personnel who were deployed to the Persian Gulf in the 1990–91 conflict are currently afflicted with the chronic multi-symptom illness known as Gulf War Illness (GWI) [1,2,3,4,5,6]. Other chemicals that may induce GWI symptoms have been proposed, such as depleted uranium, multiple vaccinations against anthrax and botulinum, as well as exposure to low levels of nerve gas agents, including soman, sarin, and mustard gas [1,13,14,15,16,17,18] This is supported by animal studies of GW agent exposure detailing the consequences of combined exposure to various agents that demonstrated sensorimotor deficits, altered brain acetylcholine (ACh) receptor binding, and increased activation of astrocytes in the brains of exposed animals [19,20,21]. It remains unclear which neuropathological manifestations may be responsible for the neurological symptoms observed in GWI patients

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