Chronic Neurological Morbidities and Elevated Hippocampal Calcium Levels in a DFP-Based Rat Model of Gulf War Illness

Abstract

Over 20 yr have elapsed since the end of the First Gulf War, yet approximately one-third of the veterans exhibit Gulf War Illness (GWI) symptoms, particularly depression and memory impairments. Exposure to organophosphate (OP) compounds is implicated for GWI development. The role of calcium (Ca2+) signaling in learning, memory, and mood is well established and disruptions in Ca2+ homeostasis are observed in many neurological disorders. However, the status of Ca2+ homeostasis in the development of GWI behavioral impairments is not known. Male Sprague-Dawley rats were exposed to OP agent diisopropyl fluorophosphate (DFP; 0.5 mg/kg, s.c. 5 days), and at 6 mo post-DFP exposure, rats were subjected to behavioral assays for the determination of GWI neurological morbidities. Fura-2AM loaded acutely isolated hippocampal neurons were used for [Ca2+]i estimations. We observed chronic depressive symptoms and cognitive deficits in rats exposed to repeated low-dose DFP. The GWI rats also manifested elevations in hippocampal [Ca2+]i along with a significant increase in the number of neurons displaying these elevations. As Ca2+ is a major second-messenger molecule, such sustained increases in its levels could activate multiple signaling cascades and alter gene expression of proteins involved in synaptic plasticity and possibly underlie the neuronal injury and chronic morbidities in GWI.

Assessment of Ketamine and its Enantiomers in an Organophosphate-Based Rat Model for Features of Gulf War Illness

“…We therefore used a combination of behavioral assays that measure certain aspects of signs of depression that are reported in humans. In agreement with our previous studies [32][33][34], DFP-exposed rats exhibited significantly higher immobility time in the FST, did not show higher preference towards sweetened water in the SPT, and exhibited lowered exploration in the open-arm of the EPM. Taken together, these behaviors suggest that repeated low-dose DFP exposure produces chronic neuropsychiatric signs in rodents.…”

“…The activity of eEF2 kinase, also known as CamKIII, is modulated by calcium and calmodulin. We recently demonstrated that hippocampal neurons from GWI rats exhibited chronic calcium elevations [33,34]. It will be interesting to investigate the role of KET on GWI calcium homeostatic mechanisms and its subsequent effect on modulating the rapid behavioral response in this model.…”

“…DFP exposures were carried out as described previously [32][33][34]. Briefly, rats were injected with DFP (0.5 mg/kg) once daily for 5 days, while control rats received DFP vehicle injections (PBS) for the same period.…”

“…These DFP rats also exhibit protracted neuronal calcium elevations and hippocampal injury [32]. This pre-clinical OP-based rat model has been helpful in identifying mechanisms underlying the development of GWI and has been used to screen drugs that could prove to be effective therapies for treatment of GWI [33]. In this study, we utilized this DFP-based rat model for GWI-like neurological morbidities to investigate whether treatment with racemic KET (R, S KET) or its individual enantiomers (R-KET, S-KET) could produce the same reported rapid-onset and long-lasting antidepressant-like effects following GW-relevant OP exposure.…”

Oligodendrocyte involvement in Gulf War Illness

“…Key diagnostic features of GWI include musculoskeletal pain, impaired cognitive functioning, disturbances of mood, and debilitating fatigue; symptoms that have persisted over time (Binns et al, 2008;Maule et al, 2018;White et al, 2016). GWI animal models replicate many of these symptoms (Zakirova et al, 2016), including impaired working memory (Phillips & Deshpande, 2018) and social memory (Zakirova et al, 2016). The established animal model of GWI includes treatment with corticosterone (Cort) for 7 days before exposure to diisopropyl fluorophosphate (DFP), an irreversible AChE inhibitor used as a proxy for sarin nerve gas (Koo et al, 2018;O'Callaghan, Kelly, Locker, Miller, & Lasley, 2015;Zakirova et al, 2016).…”