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Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutation in the X-linked  MECP2  gene, encoding methyl-CpG-binding protein 2. We have created a mouse model (  Mecp2  A140V “knock-in” mutant) expressing the recurrent human  MECP2  A140V mutation linked to an X-linked mental retardation/Rett syndrome phenotype. Morphological analyses focused on quantifying soma and nucleus size were performed on primary hippocampus and cerebellum granule neuron (CGN) cultures from mutant (  Mecp2   A140V/y ) and wild type (  Mecp2   +/y ) male mice. Cultured hippocampus and cerebellar granule neurons from mutant animals were significantly smaller than neurons from wild type animals. We also examined soma size in hippocampus neurons from individual female transgenic mice that express both a mutant  (maternal allele) and a wild type  Mecp2  gene linked to an eGFP transgene (paternal allele). In cultures from such doubly heterozygous female mice, the size of neurons expressing the mutant (A140V) allele also showed a significant reduction compared to neurons expressing wild type MeCP2, supporting a cell-autonomous role for MeCP2 in neuronal development. IGF-1 (insulin growth factor-1) treatment of neuronal cells from  Mecp2  mutant mice rescued the soma size phenotype. We also found that  Mecp2      mutation leads to down-regulation of the mTOR signaling pathway, known to be involved in neuronal size regulation. Our results suggest that i) reduced neuronal size is an important  in vitro  cellular phenotype of  Mecp2  mutation in mice, and ii) MeCP2 might play a critical role in the maintenance of neuronal structure by modulation of the mTOR pathway. The definition of a quantifiable cellular phenotype supports using neuronal size as a biomarker in the development of a high-throughput,  in vitro  assay to screen for compounds that rescue small neuronal phenotype (“phenotypic assay”).

Reduced neuronal size and mTOR pathway activity in the Mecp2 A140V Rett syndrome mouse model