Repeated contact with subtoxic soman leads to synaptic vulnerability in hippocampus.
Soman, an anticholinesterase and dangerous nerve agent, produces convulsions, memory impairment, and cell loss in the brain, especially in the hippocampus. Soman-induced accumulation of acetylcholine initiates mechanisms responsible for the development of incapacitating seizures. The prolonged epileptiform nature of these seizures causes the release of another excitatory neurotransmitter, glutamate, which has been linked to the toxic action of the nerve agent. Here, we tested whether subtoxic soman exposures influence the brain's sensitivity to glutamate-based excitotoxicity. Over a 1-week period, hippocampal slice cultures were exposed daily to a transient level of soman that produced no evidence of synaptic deterioration. After the subtoxic soman treatments, however, the tissue became vulnerable to a brief episode of glutamate receptor overstimulation that normally resulted in little or no excitotoxic damage. In those slice cultures treated with subtoxic soman, a decline in synaptic markers as well as an increase in spectrin breakdown occurred 24 hr after the mild excitotoxic event. Exposure to high soman concentrations alone produced similar synaptic degeneration, but without evident cell death, suggesting that synaptic decline is an early neurotoxicological response to the nerve agent. Interestingly, enhanced excitotoxic sensitivity caused the brain tissue to become susceptible to disparate insults initiated before or after the soman contact. These findings indicate that seemingly innocuous soman exposures leave the hippocampus sensitive to the types of insults implicated in traumatic brain injury and stroke. They also warn that asymptomatic contact with soman may lead to progressive synaptopathogenesis and that early indicators of soman exposure are critical to prevent potential brain injury.
Munirathinam
Subramani
S
Department of Pharmaceutical Sciences, Center for Drug Discovery, University of Connecticut, Storrs, Connecticut 06269, USA.
Bahr
Ben A
BA
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D001927:Brain Diseases / Q000139:chemically induced*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009557:Nipecotic Acids / Q000378:metabolism; D009924:Organ Culture Techniques; D010879:Piperazines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D012999:Soman / Q000633:toxicity*; D013194:Staining and Labeling / Q000379:methods; D013569:Synapses / Q000187:drug effects*; D016708:Synaptophysin / Q000378:metabolism; D014298:Trimethyltin Compounds / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D002800:Cholinesterase Inhibitors; D018690:Excitatory Amino Acid Agonists; D009557:Nipecotic Acids; D010879:Piperazines; D018091:Receptors, AMPA; D012999:Soman; D016708:Synaptophysin; D014298:Trimethyltin Compounds; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C046488:trimethyltin; C063976:N,N'-bis(1-decylnipecotoyl)piperazine