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Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice

Nature volume 438, pages 662–666 (2005)Cite this article

Abstract

Anxiety and fear are normal emotional responses to threatening situations. In human anxiety disorders—such as panic disorder, obsessive–compulsive disorder, post-traumatic stress disorder, social phobia, specific phobias and generalized anxiety disorder—these responses are exaggerated. The molecular mechanisms involved in the regulation of normal and pathological anxiety are mostly unknown. However, the availability of different inbred strains of mice offers an excellent model system in which to study the genetics of certain behavioural phenotypes1,2,3. Here we report, using a combination of behavioural analysis of six inbred mouse strains with quantitative gene expression profiling of several brain regions, the identification of 17 genes with expression patterns that correlate with anxiety-like behavioural phenotypes. To determine if two of the genes, glyoxalase 1 and glutathione reductase 1, have a causal role in the genesis of anxiety, we performed genetic manipulation using lentivirus-mediated gene transfer. Local overexpression of these genes in the mouse brain resulted in increased anxiety-like behaviour, while local inhibition of glyoxalase 1 expression by RNA interference decreased the anxiety-like behaviour. Both of these genes are involved in oxidative stress metabolism, linking this pathway with anxiety-related behaviour.

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Figure 1: Inbred mouse strains have different levels of anxiety-related behaviours.
Figure 2: Glyoxalase 1 (Glo1) and glutathione reductase 1 (Gsr) regulate anxiety-like behaviour in inbred mouse strains.

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Acknowledgements

We thank Information Management Consultants and Teradata (NCR) for donating and programming of the TeraGenomics database; Dan Lockhart, M. Zapala and N. Schork for software development and statistical analysis; B. Stoveken for brain dissections; J. Airas for plasmid cloning; N. Tonnu for lentivirus production; F. Bloom, J. Reilly, W. Young, W. Vale and T. Carter for their insight; and members of the Barlow laboratory for discussions and technical assistance. This work was supported by grants from NIMH (to C.B. and D.J.L.), NINDS (to C.B.) and the Academy of Finland (to I.H.). Author Contributions D.J.L. and C.B. conceived of and initiated the project. I.H., D.J.L. and C.B. designed the research. I.H. and R.S.T. performed the microarray, enzyme activity, sequencing and real-time qPCR experiments. I.H. and R.H. performed the behavioural analyses and lentivirus injections. I.H., J.M.R., J.A.E. and C.B. designed and J.M.R. performed the in situ hybridization experiments. I.H., R.A.M., O.S., I.M.V. and C.B. designed the lentivirus experiment, and R.A.M., O.S. and I.M.V. contributed the lentivirus vectors. I.H., E.E.S., C.B. and D.J.L. analysed the data. I.H., E.E.S., D.J.L. and C.B. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Authors and Affiliations

  1. The Salk Institute for Biological Studies, Laboratory of Genetics, 10010 North Torrey Pines Road, California, 92037, La Jolla, USA

    Iiris Hovatta, Richard S. Tennant, Robert Helton, Robert A. Marr, Oded Singer, Julie A. Ellison, Inder M. Verma, David J. Lockhart & Carrolee Barlow

  2. BrainCells Inc., 10835 Road to the Cure, California, 92121, San Diego, USA

    Robert Helton & Carrolee Barlow

  3. Neurome Inc., 11149 North Torrey Pines Road, California, 92037, La Jolla, USA

    Jeffrey M. Redwine

  4. Rosetta Inpharmatics LLC, Merck & Co., 12040 115th Avenue Northeast, Washington, 98109, Seattle, USA

    Eric E. Schadt

  5. Co., 12040 115th Avenue Northeast

    Eric E. Schadt

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  1. Iiris Hovatta
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Corresponding author

Correspondence to Carrolee Barlow.

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Competing interests

Microarray data have been deposited in the NCBI Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/) and are accessible through the GEO series accession number GSE3327. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure 1

This figure shows a strategy used in this study to identify candidate genes for anxiety by combining behavioral, gene expression, and functional analyses. (JPG 276 kb)

Supplementary Figure 2

This figure shows results from the real-time qPCR and enzyme activity assays for anxiety candidate genes identified by gene expression profiling. (JPG 413 kb)

Supplementary Figure 3

This figure shows the vectors used in the lentivirus-mediated gene transfer, as well as immunohistochemistry and in situ hybridization pictures of lentivirus-injected brain. (JPG 2904 kb)

Supplementary Figure 4

This figure shows a Western blot analysis of various siRNA constructs of Glo1. (JPG 861 kb)

Supplementary Table 1

This table shows the false discovery rate calculations for the gene expression analysis. (XLS 21 kb)

Supplementary Table 2

This table shows detailed results of the probe sets that correlate with the anxiety phenotype from the gene expression profiling study. (XLS 22 kb)

Supplementary Data

This document provides additional data of the behavioral analysis, and the sequencing information of Glo1 and Gsr. (DOC 29 kb)

Supplementary Methods

This document provides additional information of the methods used in this study. (DOC 107 kb)

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Hovatta, I., Tennant, R., Helton, R. et al. Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Nature 438, 662–666 (2005). https://doi.org/10.1038/nature04250

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