Doublecortin-expressing cells are selectively altered in the piriform cortex but not in neurogenic areas of symptomatic Mecp2-heterozygous mice

Rett Syndrome (RTT) is a neurodevelopmental disorder which mainly affects girls, leading to profound impairments in motor function, loss of speech, intellectual disability, and epilepsy, among other symptoms. Most cases are caused by mutations in the X-linked MECP2 gene, which encodes the protein methyl-CpG-binding protein 2 (MeCP2), an epigenetic reader with a crucial function in the regulation of neural maturation. Previously, using the marker of immature neurons doublecortin (DCX), we showed that a population of embryonic-born neurons of the piriform cortex, which experience prolonged maturation throughout life, was increased in the piriform cortex of young adult (2 months old), symptomatic, Mecp2 -null male mice. By contrast, these cells were not affected in age matched Mecp2 -heterozygous female mice, who are pre-symptomatic at that age. To determine whether symptom onset would affect DCX-expressing neurons, in this study we analysed samples from 6 months old, symptomatic Mecp2 -heterozygous female mice. Our results show a specific increase in the density of DCX-positive neurons in the piriform cortex, consistent with observations in males. However, no differences were detected in the neurogenic niches of the dentate gyrus or the ventricular-subventricular zone when compared to their wild-type controls. Further, morphological analyses of the DCX-expressing cells of the piriform cortex reveal that they are smaller and show less complex dendritic branching in mutant mice. In conclusion, our findings support a role of MeCP2 in the maturation process of the embryonic-born DCX neurons in the piriform cortex and point to region-specific alterations in neuronal maturation in RTT.