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

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, however, 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 the heightened anxiety and social behavior deficits, we analyzed MECP2 duplication mice (MECP2-TG1) with reduced Crh and Oprm1 levels. In MECP2-TG1 animals, reducing Crh, or its receptor, Crhr1, suppresses anxiety-like behavior; in contrast, reducing Oprm1 improves abnormal social behavior. These data demonstrate that increased MeCP2 levels impact molecular pathways underlying anxiety and social behavior, and provide novel insight into potential therapies for MECP2-related disorders.