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Effect of Acute Soman Exposure on GABAA Receptors in Rat Hippocampal Slices and Cultured Hippocampal Neurons

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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 GABAA 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 GABAA receptors in cultured rat hippocampal neurons. The effect of soman on GABAAR endocytosis was not due to inhibition of acetylcholinesterase (AChE) because (1) the acetylcholine muscarinic receptor antagonist atropine did not block soman-induced GABAAR endocytosis; and (2) physostigmine, at concentrations that completely inhibit AChE activity, did not cause GABAAR endocytosis. Moreover, blocking of the N-methyl-d-aspartate (NMDA) receptors by 2-amino-5-phosphonovalerate (APV) had no effect on soman-induced GABAAR 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 GABAAR endocytosis may have significant implications in the development of effective countermeasures against soman-induced seizures.

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Authors and Affiliations

  1. Defence R&D Canada-Suffield, Station Main, Medicine Hat, P.O. Box 4000, Alberta, T1A 8K6, Canada

    Yushan Wang, Tracy Weiss, Christine Stewart & John Mikler

  2. Brain Research Centre, University of British Columbia, Vancouver, BC, Canada

    Lidong Liu

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  1. Yushan Wang
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  2. Lidong Liu
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  3. Tracy Weiss
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  4. Christine Stewart
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Correspondence to Yushan Wang.

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Wang, Y., Liu, L., Weiss, T. et al. Effect of Acute Soman Exposure on GABAA Receptors in Rat Hippocampal Slices and Cultured Hippocampal Neurons. Neurotox Res 20, 343–350 (2011). https://doi.org/10.1007/s12640-011-9248-9

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  • DOI: https://doi.org/10.1007/s12640-011-9248-9

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