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

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

doi:10.1371/journal.pone.0119579

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

PLoS One. 2015 Mar 18;10(3):e0119579. doi: 10.1371/journal.pone.0119579. eCollection 2015.

Authors

Affiliations

¹ The Roskamp Institute, Sarasota, Florida, United States of America; The Open University, Walton Hall, Milton Keynes, Buckinghamshire, United Kingdom; James A. Haley Veteran's Hospital, Tampa, Florida, United States of America.
² The Roskamp Institute, Sarasota, Florida, United States of America; The Open University, Walton Hall, Milton Keynes, Buckinghamshire, United Kingdom.
³ The Roskamp Institute, Sarasota, Florida, United States of America; James A. Haley Veteran's Hospital, Tampa, Florida, United States of America.
⁴ University of Miami Miller School of Medicine, Miami, Florida, United States of America.
⁵ The Roskamp Institute, Sarasota, Florida, United States of America.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Astrocytes / drug effects
Astrocytes / metabolism
Astrocytes / pathology
Cerebral Cortex / drug effects
Cerebral Cortex / metabolism
Cerebral Cortex / pathology
Cerebral Cortex / physiopathology*
Cognition / drug effects
Disease Models, Animal
Gene Expression
Gulf War
Hippocampus / drug effects
Hippocampus / metabolism
Hippocampus / pathology
Hippocampus / physiopathology*
Humans
Male
Memory, Long-Term / drug effects*
Memory, Short-Term / drug effects
Mice
Mice, Inbred C57BL
Permethrin / toxicity*
Persian Gulf Syndrome / chemically induced
Persian Gulf Syndrome / metabolism
Persian Gulf Syndrome / pathology
Persian Gulf Syndrome / physiopathology*
Pyridostigmine Bromide / toxicity*
Synaptophysin / antagonists & inhibitors
Synaptophysin / genetics
Synaptophysin / metabolism
Time Factors

Substances

Synaptophysin
Syp protein, mouse
Permethrin
Pyridostigmine Bromide

Grants and funding

This research was funded by a Congressionally Directed Medical Research Program award to Dr. Ait-Ghezala (GW100076), VA merit award to Dr. Fiona Crawford and by the Roskamp Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.