Lack of MeCP2 leads to region-specific increase of doublecortin in the olfactory system

Abstract

The protein doublecortin is mainly expressed in migrating neuroblasts and immature neurons. The Xlinked gene MECP2, associated to several neurodevelopmental disorders such as Rett Syndrome, encodes the protein methyl-CpG-binding protein 2 (MeCP2), a regulatory protein that has been implicated in neuronal maturation and refinement of olfactory circuits. Here we explored doublecortin immunoreactivity in the brain of young-adult female Mecp2-heterozygous and male Mecp2-null mice and their wild-type littermates. The distribution of doublecortin-immunorective somata in neurogenic brain regions was consistent with previous reports in rodents, and no qualitative differences were found between genotypes or sexes. Quantitatively, we found a significant increase in doublecortin cell density in in the piriform cortex of Mecp2-null males as compared to WT littermates. A similar increase was seen in a newly-identified population of doublecortin cells in the olfactory tubercle. In these olfactory structures, however, the percentage of doublecortin immature neurons that also expressed NeuN was not different between genotypes. By contrast, we found no significant differences between genotypes in doublecortinimmunorectivity in the olfactory bulbs. Nonetheless, in the periglomerular layer of Mecp2-null males we observed a specific decrease of immature neurons co-expressing doublecortin and NeuN. Overall, no differences were evident between Mecp2-heterozygous and WT females. Also, no differences could be detected between genotypes in the density of doublecortin-immunoreactive cells in the hippocampus or striatum of either males or females. Our results suggest that MeCP2 is involved in neuronal maturation in a region-dependent manner.

Early life stress exacerbates behavioural and neuronal alterations in adolescent male mice lacking methyl-CpG binding protein 2 (Mecp2)

“…Maternal separation exacerbates the increase in the density of doublecortin -ir neurons caused by lack of Mecp2, and both maternal separation and lack of Mecp2 decrease reelin-ir in a region dependent manner Immunoreactivity to DCX, a marker of immature neurons, shows that lack of Mecp2 leads to an increase in the density of immature neurons at the Pir and the OT, similar to that we previously reported at early adulthood, 8 weeks of age (Martínez-Rodríguez et al, 2019). Further, MS uncovers an 10.3389/fnbeh.2022.974692 increase in the density of immature neurons at other regions, including the hippocampus, of adolescent Mecp2-null mice.…”

Male-specific features are reduced in Mecp2-null mice: analyses of vasopressinergic innervation, pheromone production and social behaviour

“…In this strain, hemizygous males (Mecp2-null) are infertile, so the breeding pairs are established with Mecp2-heterozygous (Mecp2-het) females paired to WT males. This impedes the production of Mecp2-null females in this strain, and hence, in this study, we compare males and females separately, as we did in a previous study (Martínez-Rodríguez et al 2019).…”

Region-specific KCC2 rescue by rhIGF-1 and oxytocin in a mouse model of Rett syndrome

“…2 ). We selected several areas of the olfactory system (the main olfactory bulb - MOB, anterior olfactory nucleus - AON, medial part of the anterior olfactory nucleus – AONm, and the anterior part of the piriform cortex – aPIR), as olfactory function and circuitry maturation is altered by the lack of MeCP2 (Degano et al 2014; Martínez-Rodríguez et al 2019). The olfactory system is fundamental for social behavior in rodents, and all the aforementioned regions express high levels of OXTR (Gigliucci et al 2014; Huang et al 2014).…”

“…Another possibility is that the lack of MeCP2 in sensory cortices makes them more immature, extending rhIGF-1’s therapeutic window, a prospect considered earlier (Banerjee et al 2019). It has been shown that the loss of MeCP2 causes immaturity in selected areas of the olfactory system, including the piriform cortex (Martínez-Rodríguez et al, 2019). The KCC2 expression profile we report here is in line with this region-selective immaturity.…”