Enhanced Neuronal Ras Activation Influences the Adverse Phenotype in a Mouse Model of Rett Syndrome

The neurological disorder Rett syndrome (RTT) is caused by mutations in the X-linked gene of Methyl CpG binding protein 2 (MeCP2). RTT is characterized by an apparently asymptomatic postnatal development followed by a period of regression, with progressive loss of motor capabilities, language, and cognitive function. MeCP2-Knockout mouse models mimic key clinical features of RTT, including developmental regression leading to motor impairment, irregular breathing, and early mortality. Expression of MeCP2 increases during postnatal development with neuronal maturation, and this correlates with the onset of RTT symptoms. In order to investigate the potential effects of neuronal Ras activity in RTT, we crossbred MeCP2-KO mice and transgenic mice expressing activated human Val12 Ha-Ras selectively in neurons (Heumann et al. 2000). The crossbreeding of heterozygous MeCP2^+/--females with transgenic synRas-males caused a dramatically increased lethality. Furthermore, in contrast to heterozygous MeCP^-/y-males double transgenic synRas/MeCP^-/y-males did not survive beyond postnatal day 28. However, double transgenic female mice developed an enhanced anxiety-like behaviour in the elevated plus maze comparable to that of the strongly affected MeCP2^-/y-males. Our findings showed that enhanced neuronal Ras activity aggravates the RTT phenotype in an animal model of RTT. The results are discussed in the context of the otherwise protective function of neuronal Ras activation found previously in chemical and mechanical lesion models (Heumann et al. 2000).