Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity

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Abstract

Neuropathy target esterase (NTE) is involved in neural development and is the target for neurodegeneration induced by selected organophosphorus pesticides and chemical warfare agents. We generated mice with disruptions in Nte, the gene encoding NTE. Nte−/− mice die after embryonic day 8, and Nte+/− mice have lower activity of Nte in the brain and higher mortality when exposed to the Nte-inhibiting compound ethyl octylphosphonofluoridate (EOPF) than do wild-type mice. Nte+/− and wild-type mice treated with 1 mg per kg of body weight of EOPF have elevated motor activity, showing that even minor reduction of Nte activity leads to hyperactivity. These studies show that genetic or chemical reduction of Nte activity results in a neurological phenotype of hyperactivity in mammals and indicate that EOPF toxicity occurs directly through inhibition of Nte without the requirement for Nte gain of function or aging.

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Figure 1: Characterization of the NTE and Nte genomic loci and identification of NTE-R1.
Figure 2: Generation of mice with disruptions in Nte.
Figure 3: Nte−/− mice are not viable beyond E8.
Figure 4: Nte is highly expressed in developing spinal cord and lens and in specific regions of the adult brain and testes.
Figure 5: Nte+/− mice had lower activity of Nte but not acetylcholinesterase.
Figure 6: Nte+/− mice were more sensitive to organophosphate toxicity and showed greater motor activity.

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Acknowledgements

The authors thank L. Garrett, J. Cheng, Y. Dayn and K-F. Lee for assistance in generating transgenic mice, D. Wangsa for assistance with cytogenetic analyses, R. Helton for animal husbandry, E. Annas for technical support and B. Cravatt and S. Heinemann for comments and experimental advice. This work was supported by the Canadian Institutes of Health Research (C.J.W.), the US National Institute of Environmental Health Sciences, the US National Institutes of Health (J.E.C), the Department of Defense (US Army Medical Research and Material Command) and the Frederick B. Rentschler Endowed Chair (C.B.).

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Correspondence to Carrolee Barlow.

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Winrow, C., Hemming, M., Allen, D. et al. Loss of neuropathy target esterase in mice links organophosphate exposure to hyperactivity. Nat Genet 33, 477–485 (2003) doi:10.1038/ng1131

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