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 (Ca 2+) signaling in learning, memory, and mood is well established and disruptions in Ca 2+ homeostasis are observed in many neurological disorders. However, the status of Ca 2+ 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 [Ca 2+ ] 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 [Ca 2+ ] i along with a significant increase in the number of neurons displaying these elevations. As Ca 2+ 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.