What's done can sometimes be undone. Parents worry that by the time a child shows symptoms of a neurodevelopmental disorder like autism, irreversible damage has been done to the brain. Rett syndrome, which is similar to autism, causes cognitive and motor decline after seemingly normal infant development. Guy et al. report that, even after symptom onset, the neurological phenotype can be reversed in a mouse model of Rett syndrome in a recent article in Science.
Rett syndrome is caused by mutation of the X-linked gene encoding methyl-CpG-binding protein, MeCP2, and predominantly affects girls. Most girls with Rett syndrome lose muscle tone and the ability to speak within six to eighteen months of birth. Unlike girls with Rett syndrome, who can survive into adulthood, boys with MeCP2 mutations have more severe phenotypes that can be fatal.
To disrupt Mecp2 in mice, the authors inserted a Stop cassette flanked by recombination sites into the mouse Mecp2 gene. They generated a second line of mice expressing cre recombinase linked to a modified version of the estrogen receptor that only responds to the selective estrogen receptor modulator tamoxifen (cre-ER). Then they crossed these two mouse lines, producing mice deficient of Mecp2 in the absence of tamoxifen. However, in the presence of tamoxifen, the Stop cassette is excised and Mecp2 expression restored.
In addition to cognitive deficits, Rett syndrome causes neurological decline, marked by difficulty moving and breathing. The authors measured the mobility, gait, hindlimb clasping, tremor, breathing and general health of the mice. Male mice carrying the Stop cassette in Mecp2 (Stop/y) developed neurological symptoms at six weeks of age, which progressively worsened until their death by seventeen weeks of age. In contrast, more than 80% of twelve-week old Stop/y-cre mice treated once per week with tamoxifen survived virtually symptom-free.
Girls with Rett syndrome carry mutations in one MeCP2 allele and therefore show mosaic expression of MeCP2 protein. Heterozygous Stop/+ female mice developed neurological symptoms at four to twelve months of age. However, after five weeks of tamoxifen treatment, symptomatic Stop/+,cre mice behaved similarly to wild-type mice. Therefore, even after the onset of symptoms, treatment compensated for Mecp2 deficiency, suggesting that Rett syndrome does not permanently disrupt neuronal development.
Although these data suggest that MeCP2 supplementation reverses the effects of Rett syndrome, MeCP2 gene therapy is an unlikely treatment for girls with Rett syndrome. Like MeCP2 deficiency, excess MeCP2 can be damaging. Consistent with previous studies of mice overexpressing Mecp2, more than 50% of Stop/y,cre mice treated with daily injections of tamoxifen died, suggesting that rapid and widespread overexpression of MeCP2 can be dangerous.