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Human Molecular Genetics Advance Access originally published online on April 1, 2008
Human Molecular Genetics 2008 17(13):2047-2057; doi:10.1093/hmg/ddn102
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits

Andrea M. Allan1, Xiaomin Liang1,{dagger}, Yuping Luo1, ChangHui Pak2, Xuekun Li1, Keith E. Szulwach2, Dahua Chen3, Peng Jin2 and Xinyu Zhao1,*

1 Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA 2 Department of Human Genetics and Graduate Program in Genetics and Molecular Biology, Emory University School of Medicine, Atlanta, GA 30322, USA 3 State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China

* To whom correspondence should be addressed. Tel: +1 5052724410; Fax: +1 5052728082; Email: xzhao{at}salud.unm.edu

Received February 15, 2008; Accepted March 26, 2008

Methyl-CpG binding proteins (MBDs) are central components of DNA methylation-mediated epigenetic gene regulation. Alterations of epigenetic pathways are known to be associated with several neurodevelopmental disorders, particularly autism. Our previous studies showed that the loss of Mbd1 led to reduced hippocampal neurogenesis and impaired learning in mice. However, whether MBD1 regulates the autism-related cognitive functions remains unknown. Here we show that Mbd1 mutant (Mbd1–/–) mice exhibit several core deficits frequently associated with autism, including reduced social interaction, learning deficits, anxiety, defective sensory motor gating, depression and abnormal brain serotonin activity. Furthermore, we find that Mbd1 can directly regulate the expression of Htr2c, one of the serotonin receptors, by binding to its promoter, and the loss of Mbd1 led to elevated expression of Htr2c. Our results, therefore, demonstrate the importance of epigenetic regulation in mammalian brain development and cognitive functions. Understanding how the loss of Mbd1 could lead to autism-like behavioral phenotypes would reveal much-needed information about the molecular pathogenesis of autism.

{dagger} Present address: Department of Anesthesiology, the First Affiliated Hospital of Chongqing Medical University, Youyi Road No. 1, Yuanjiagang, Chongqing 400016, China.


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