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MeCP2-mediated alterations of striatal features accompany psychomotor deficits in a mouse model of Rett syndrome

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Abstract

Rett Syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Affected individuals develop motor deficits including stereotypic hand movements, impaired motor learning and difficulties with movement. To understand the neural mechanisms of motor deficits in RTT, we characterized the molecular and cellular phenotypes in the striatum, the major input nucleus of the basal ganglia that controls psychomotor function, in mice carrying a null allele of Mecp2. These mice showed significant hypoactivity associated with impaired motor coordination and motor skill learning. We found that dopamine content was significantly reduced in the striatum of Mecp2 null mice. Reduced dopamine was accompanied by down-regulation of tyrosine hydroxylase and up-regulation of dopamine D2 receptors, particularly in the rostral striatum. We also observed that loss of MeCP2 induced compartment-specific alterations in the striatum, including reduced expression of μ-opioid receptors in the striosomes and increased number of calbindin-positive neurons in the striatal matrix. The total number of parvalbumin-positive interneurons and their dendritic arborization were also significantly increased in the striatum of Mecp2 null mice. Together, our findings support that MeCP2 regulates a unique set of genes critical for modulating motor output of the striatum, and that aberrant structure and function of the striatum due to MeCP2 deficiency may underlie the motor deficits in RTT.

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Acknowledgments

We thank Dr. Jin-Chung Chen and Dr. Ming-Ji Fann for critical reading of the manuscript, and Dr. Chih-Chang Chao for technical consultation. This study was supported by National Science Council of Taiwan (NSC99-2320-B-004-001-MY2, NSC100-2320-B-004-001, NSC101-2320-B-004-003-MY2).

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The authors declare that they have no conflict of interest.

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  1. Institute of Neuroscience, National Cheng-Chi University, 64, Sec. 2, Chi-Nan Road, Wen-Shan District, Taipei, 11605, Taiwan

    Fang-Chi Kao, San-Hua Su & Wenlin Liao

  2. Research Center for Mind, Brain and Learning, National Cheng-Chi University, Taipei, 11605, Taiwan

    Wenlin Liao

  3. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Gregory C. Carlson

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  1. Fang-Chi Kao
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  2. San-Hua Su
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Correspondence to Wenlin Liao.

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F.-C. Kao and S.-H. Su contributed equally to this work.

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Kao, FC., Su, SH., Carlson, G.C. et al. MeCP2-mediated alterations of striatal features accompany psychomotor deficits in a mouse model of Rett syndrome. Brain Struct Funct 220, 419–434 (2015). https://doi.org/10.1007/s00429-013-0664-x

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