Glutamate Receptor Pathology is Present in the Hippocampus Following Repeated Sub-Lethal Soman Exposure in the Absence of Spatial Memory Deficits

摘要

Much is still unknown about the long-term effects of repeated, sub- lethal exposure to organophosphorus (OP) nerve agents, such as soman (GD), on learning and memory tasks and related protein expression in the hippocampus. In the present study, guinea pigs were exposed to sub-lethal doses of GD for 10 days and cognitive performance assessed using the Morris water maze (MWM) up to 88 days post-exposure to investigate spatial learning. Additionally, hippocampal lysates were probed for cytoskeletal, synaptic and glutamate receptor proteins using Western blot analyses. No significant difference in MWM performance was observed between repeated sub-lethal GD exposed and saline control groups. However, Western blot analyses revealed significant changes in glutamate receptor protein immunoreactivity for subunits GluR2, NMDAR1, NMDAR2a and NMDAR2b in the hippocampi of GD-exposed guinea pigs. Levels of GluR2, NMDAR2a and NMDAR2b increased by 3 months post-initial exposure and returned to control levels by 6 months while NMDAR1 decreased by 6 months. No significant differences in neurofilament medium (NFM), neurofilament light (NFL) or synaptophysin densitometry were detected and a-II-spectrin proteolytic breakdown was also absent. These results reveal that repeated, sub-lethal exposure to GD affects glutamate receptor subunit expression but does not affect cytoskeletal protein immunoreactivity or the proteolytic state in the hippocampus. Though these changes do not affect spatial memory, they may contribute to other cognitive deficits previously observed following sub-lethal OP exposure.