title: Glutamate receptor pathology is present in the hippocampus following repeated sub-lethal soman exposure in the absence of spatial memory deficits.
abstract: 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 alpha-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.
authors.affiliation: US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Comparative Medicine Division, Comparative Pathology Branch, Aberdeen Proving Ground, MD 21010-5400, USA. erik.a.johnson1@us.army.mil
authors.forename: Erik A
authors.initials: EA
authors.lastname: Johnson
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Daugherty
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Gallagher
authors.forename: Anita V
authors.initials: AV
authors.lastname: Moran
authors.forename: S Michelle
authors.initials: SM
authors.lastname: DeFord
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006168:Guinea Pigs; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007928:Lethal Dose 50; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced; D021122:Protein Subunits / Q000378:metabolism; D017470:Receptors, Glutamate / Q000145:classification / Q000378:metabolism*; D012999:Soman / Q000494:pharmacology*; D013037:Spatial Behavior / Q000187:drug effects; D013997:Time Factors
chemical_list: D002619:Chemical Warfare Agents; D021122:Protein Subunits; D017470:Receptors, Glutamate; D012999:Soman