Calcium Hypothesis of Gulf War Illness: Role of Calcium Ions in Neurological Morbidities in a DFP-Based Rat Model for Gulf War Illness

Gulf War Illness (GWI) refers to a multi-system disorder that afflicts approximately 30% of First Gulf War (GW) veterans. Amongst the symptoms exhibited, mood and memory impairment are commonly reported by GW veterans. Exposure to organophosphate (OP) compounds which target the cholinergic system is considered a leading cause for GWI symptoms. It is hypothesized that chronic OP-based war-time stimulation of cholinergic signaling led to recruitment of excitatory glutamatergic signaling and other downstream signaling cascades leading to neuronal injury, neuroinflammation, generation of reactive oxygen species, oxidative stress, and mitochondrial damage within the central nervous system. These findings have been observed in both experimental models and GWI veterans. In this context the role of calcium (Ca2+) signaling in GWI has come to the forefront. Here we present our Ca2+ hypothesis of GWI that suggests sustained neuronal Ca2+ elevations serve as a molecular trigger for pathological synaptic plasticity that has allowed for the persistence of GWI symptoms. Subsequently we discuss that therapeutic targeting of Ca2+ homeostatic mechanisms provides novel targets for effective treatment of GWI-related neurological signs in our rodent model.