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Crh and Oprm1 mediate anxiety-related behavior and social approach in a mouse model of MECP2 duplication syndrome

Nature Genetics volume 44, pages 206–211 (2012)Cite this article

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Abstract

Genomic duplications spanning Xq28 are associated with a spectrum of phenotypes, including anxiety and autism. The minimal region shared among affected individuals includes MECP2 and IRAK1, although it is unclear which gene when overexpressed causes anxiety and social behavior deficits. We report that doubling MECP2 levels causes heightened anxiety and autism-like features in mice and alters the expression of genes that influence anxiety and social behavior, such as Crh and Oprm1. To test the hypothesis that alterations in these two genes contribute to heightened anxiety and social behavior deficits, we analyzed MECP2 duplication mice (MECP2-TG1) that have reduced Crh and Oprm1 expression. In MECP2-TG1 animals, reducing the levels of Crh or its receptor, Crhr1, suppressed anxiety-like behavior; in contrast, reducing Oprm1 expression improved abnormal social behavior. These data indicate that increased MeCP2 levels affect molecular pathways underlying anxiety and social behavior and provide new insight into potential therapies for MECP2-related disorders.

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Figure 1: Increasing the endogenous levels of MeCP2 causes heightened anxiety-like behavior in mice.
Figure 2: Increasing the endogenous levels of MeCP2 causes social behavior deficits in mice.
Figure 3: Gene expression analysis of the amygdala identifies a subset of altered genes implicated in anxiety and/or social behavior.
Figure 4: Genetic reduction of Crh improves anxiety-like behavior in MECP2 duplication mice.
Figure 5: Genetic reduction of the CRH receptor, Crhr1, and pharmacologic intervention using a CRHR1 antagonist improve anxiety-like behavior in MECP2 duplication mice.
Figure 6: Genetic reduction of Oprm1 improves the social behavior deficits of MECP2 duplication mice.

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Acknowledgements

We thank M. Ramocki and J. Neul for critical reading of the manuscript, C. Spencer, R. Paylor and P. Moretti for advice on neurobehavioral tasks, the Baylor College of Medicine (BCM) Microarray core and the BCM Intellectual and Developmental Disabilities Research Center (IDDRC) RNA In Situ and Mouse Neurobehavior cores for use of their facilities. This work was funded by grants from the US National Institutes of Health (NS043124 to R.C.S.; NS073317 to C.M.M.; NS057819 to H.Y.Z.; and HD24064 to H.Y.Z. and the BCM IDDRC), the Autism Speaks (Predoctoral Fellowship to R.C.S.), the Carl C. Anderson, Sr. and Marie Jo Anderson Charitable Foundation, the Simons Foundation and the Rett Syndrome Research Trust (to H.Y.Z.). H.Y.Z. is a Howard Hughes Medical Institute investigator.

Author information

Author notes

  1. Caleigh Mandel-Brehm

    Present address: Current address: Department of Neuroscience, Division of Medical Sciences, Harvard University, Boston, Massachusetts, USA.,

  2. Bryan E McGill

    Present address: Current address: Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri, USA.,

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    Rodney C Samaco, Caleigh Mandel-Brehm, Chad A Shaw & Huda Y Zoghbi

  2. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA

    Rodney C Samaco, Christopher M McGraw & Huda Y Zoghbi

  3. Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA

    Christopher M McGraw & Huda Y Zoghbi

  4. Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA

    Bryan E McGill & Huda Y Zoghbi

  5. Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, Texas, USA

    Huda Y Zoghbi

  6. Howard Hughes Medical Institute, Houston, Texas, USA

    Huda Y Zoghbi

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Contributions

R.C.S., C.M.-B. and C.M.M. performed experiments. R.C.S. and C.M.M. analyzed the data. C.A.S. performed statistical analyses of microarray data. B.E.M. provided intellectual contribution to and initiated CRH genetic interaction studies. R.C.S. and H.Y.Z. designed experiments, reviewed the data and wrote the manuscript. All authors reviewed the manuscript in its preparation.

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Correspondence to Huda Y Zoghbi.

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Samaco, R., Mandel-Brehm, C., McGraw, C. et al. Crh and Oprm1 mediate anxiety-related behavior and social approach in a mouse model of MECP2 duplication syndrome. Nat Genet 44, 206–211 (2012). https://doi.org/10.1038/ng.1066

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