While the first derivation of Rett syndrome hiPSC lines with known mutations in MECP2 was performed by Hotta et al. in 2009 71, to our knowledge, the first of these models accompanied by extensive phenotypic characterization and later corroborated by other groups was created by Marchetto et al. who in 2010 derived hiPSCs from the fibroblasts of RTT patients with MECP2 mutations. They found that RTT patient-derived neurons had fewer synapses, reduced spine density, and smaller cell body compared to wild type (WT) controls. Furthermore cultures had a reduced density of the glutamate transporter VGLUT1 on glutamatergic neurons. Knockdown of MECP2, that is the reduction of the expression of the MECP2 gene so as to mimic RTT patient-derived neurons, in WT hiPSCs resulted in a similar glutamate transporter phenotype. Overexpression of MECP2 in WT and RTT patient-derived neurons resulted in increased density of VGLUT1, suggesting a dose-dependent relationship between the MECP2 gene and glutamate transport. Interestingly, overexpression of MECP2 is also pathogenic, and recently, a primate model of MECP2 overexpression showing autism-like social deficit has been generated72. A human hiPSC
