Elsevier

Biological Psychiatry

Volume 59, Issue 5, 1 March 2006, Pages 468-476
Biological Psychiatry

Original article
Postnatal Loss of Methyl-CpG Binding Protein 2 in the Forebrain is Sufficient to Mediate Behavioral Aspects of Rett Syndrome in Mice

https://doi.org/10.1016/j.biopsych.2005.07.025Get rights and content

Background

Mutations in the methyl-CpG binding protein 2 (MeCP2) gene cause Rett syndrome (RTT), a neurodevelopmental disorder that is accompanied by a broad array of behavioral phenotypes, mainly affecting females. Methyl-CpG binding protein 2 is a transcriptional repressor that is widely expressed in all tissues.

Methods

To investigate whether the postnatal loss of MeCP2 in the forebrain is sufficient to produce the behavioral phenotypes observed in RTT, we have generated conditional MeCP2 knockout mice.

Results

These mice display behavioral abnormalities similar to RTT phenotypes, including hindlimb clasping, impaired motor coordination, increased anxiety, and abnormal social behavior with other mice. These mice, however, have normal locomotor activity and unimpaired context-dependent fear conditioning, suggesting that the behavioral deficits observed are the result of loss of MeCP2 function in postnatal forebrain and not the result of generalized global deficits.

Conclusions

These data highlight the important role of MeCP2 in the forebrain and suggest that even partial loss of MeCP2 expression in these brain regions is sufficient to recapitulate features of RTT.

Section snippets

Generation of MeCP2 Conditional Knockout Mice

The CaMKII-Cre93 line was on a mixed 129/BALBC background that was back-crossed to a C57BL/6 line. The floxed MeCP2 was also on a similar mixed background and was back-crossed to C57BL/6 mice. Male CaMKII-Cre93 mice were crossed with female floxed MeCP2 mice, and the resulting bigenic mice exhibited no obvious initial phenotypic difference (Chen et al 2001). All experiments were performed on littermates derived from this mating paradigm to ensure analysis by matched control (CTL) mice and to

Conditional MeCP2 KO Mice Show a Selective Deletion of MeCP2 in Forebrain Regions

To determine the regional distribution of the MeCP2 deletion in the conditional KO mice compared with CTL littermates, we used fluorescent immunohistochemistry. In all animals, the MeCP2 staining was localized to the neuronal nuclei. The conditional MeCP2 KO mice showed a clear reduction in MeCP2 staining in the prefrontal cortex, striatum, nucleus accumbens, hippocampus, and amygdala compared with the CTL littermates (Figure 1A); however, the level of MeCP2 in the habenula was unchanged

Discussion

The results presented in this study show that conditional MeCP2 KO mice display behavioral deficits that are characteristic of many features of RTT. These conditional MeCP2 KO mice have motor coordination deficits, increased anxiety, and impaired social interactions with other mice. These mice, however, have normal locomotor activity and unimpaired context-dependent fear conditioning, suggesting that the behavioral deficits observed are the result of loss of MeCP2 function in postnatal brain

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