AUTISTIC-LIKE FEATURES IN A MOUSE MODEL OF MECP2 DUPLICATION SYNDROME CORRELATE WITH ALTERED GENE NETWORKS

Background: MeCP2 duplication syndrome is a progressive neurological disorder caused by duplications of the transcriptional repressor methyl-CpG binding protein 2. Autism is a recently discovered feature common to patients with MeCP2 duplication syndrome.

Objectives: 1) To determine if the autistic features of MeCP2 duplication syndrome are reproduced by the duplication of MECP2 alone in mice, and 2) to uncover a molecular mechanism that could explain behavioral abnormalities in the MeCP2 duplication syndrome mouse models.

Methods: Autistic-like features were investigated using behavioral assays for anxiety, social interaction and communication in two mouse models that express a two-fold (Mecp2^Tg1) or three-fold (Mecp2^Tg3) increase in endogenous MeCP2. Transcriptional profiling of the cortex and hippocampus from Mecp2^Tg1 mice was performed and gene expression alterations were confirmed by quantitative PCR (qPCR). Gene network analysis of genes confirmed to be altered was used to determine the relevance of altered gene networks to the behavioral abnormalities observed in the MeCP2 duplication syndrome mouse models.

Results: Mecp2^Tg1 and Mecp2^Tg3 mice display heightened anxiety-like behavior, social behavior abnormalities and altered communication. Transcriptional profiling revealed a majority of significantly altered genes to be down-regulated. 28 of 60 gene expression changes were confirmed by qPCR. Preliminary gene network analysis suggests that MeCP2 coordinates complex gene networks that impact each other to serve particular functions relevant to behavior.

Conclusions: An increase in endogenous MeCP2 expression in mice reproduces the autistic features observed in MeCP2 duplication syndrome. The MeCP2 duplication syndrome mouse models are therefore an excellent addition to the current autism mouse models. Furthermore, gene expression profiling has identified novel candidate MeCP2 target genes that may be regulated in gene networks that serve particular functions relevant to autism. Importantly, these data underscore the importance of MeCP2 in the genetic pathways that govern normal anxiety and social behavior.