title: Effect of acute soman exposure on GABA(A) receptors in rat hippocampal slices and cultured hippocampal neurons.
abstract: Exposure of the central nervous system to organophosphorus (OP) nerve agents causes seizures and neuronal cell death. Benzodiazepines are commonly used to treat seizures induced by OPs. However, it is known that soman-induced seizures are particularly resistant to benzodiazepine treatment, as compared with other OPs. This study investigated the effect of soman on γ-aminobutyric acid (GABA) neurotransmission in acute rat hippocampal slices and the surface expression of GABA(A) receptors in cultured rat hippocampal neurons. Results showed that GABA-mediated inhibitory post synaptic currents (IPSCs) are significantly reduced by soman in a concentration-dependent manner in acute rat hippocampal slices. Furthermore, confocal microscopic and cell-based ELISA assays revealed that soman caused rapid internalization of GABA(A) receptors in cultured rat hippocampal neurons. The effect of soman on GABA(A)R endocytosis was not due to inhibition of acetylcholinesterase (AChE) because (1) the acetylcholine muscarinic receptor antagonist atropine did not block soman-induced GABA(A)R endocytosis; and (2) physostigmine, at concentrations that completely inhibit AChE activity, did not cause GABA(A)R endocytosis. Moreover, blocking of the N-methyl-D-aspartate (NMDA) receptors by 2-amino-5-phosphonovalerate (APV) had no effect on soman-induced GABA(A)R endocytosis, suggesting that the soman effect was not secondary to glutamate receptor over activation. Regardless of the exact mechanism, the observation that soman induces rapid GABA(A)R endocytosis may have significant implications in the development of effective countermeasures against soman-induced seizures.
authors.affiliation: Defence R&D Canada-Suffield, Station Main, Medicine Hat, P.O. Box 4000, Alberta T1A8K6, Canada. Yushan.Wang@drdc-rddc.gc.ca
authors.forename: Yushan
authors.initials: Y
authors.lastname: Wang
authors.forename: Lidong
authors.initials: L
authors.lastname: Liu
authors.forename: Tracy
authors.initials: T
authors.lastname: Weiss
authors.forename: Christine
authors.initials: C
authors.lastname: Stewart
authors.forename: John
authors.initials: J
authors.lastname: Mikler
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology; D001285:Atropine / Q000494:pharmacology; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D004705:Endocytosis / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D018613:Microscopy, Confocal / Q000379:methods; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D012999:Soman / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D011963:Receptors, GABA-A; C056639:2-amino-5-phosphopentanoic acid; D001285:Atropine; D012999:Soman; D014633:Valine; D003975:Diazepam