A boost in the levels of MeCP2, the gene implicated in Rett syndrome, makes mice more susceptible to seizures and subtly alters their neurons, according to a study published in the July issue of the American Journal of Pathology1.
Mutations that inactivate MeCP2 in people lead to Rett syndrome, an autism-like disorder characterized by repetitive movements and loss of language.
These results suggest that the brain is exquisitely sensitive to levels of MeCP2, which fine-tunes the expression of thousands of other genes.
In the new study, researchers engineered mice to carry an extra variant of the MeCP2 gene that expresses the protein at a lower level than the normal copy. These mice effectively have 1.5 times the amount of MeCP2 as controls do.
The mice with excess MeCP2 are more aggressive than controls are — they are quicker to attack cagemates — but otherwise have similar behaviors. They are also more sensitive than controls to a chemical, pentylenetetrazol, that induces seizures.
These mice have fewer neuronal branches than controls do and denser signal-receiving nodes called dendritic spines. These features suggest that neurons in the mutant mice are less mature than those in controls, the researchers say.
In contrast, studies have shown that mice with twice the normal amount of MeCP2 show several behavioral abnormalities, including heightened anxiety, motor deficits and a lack of interest in other mice. (People with double the normal amount of MeCP2 also show autism-like symptoms.)
These mice also have more severe neuronal defects than the mice in the new study, including a deficit in their ability to strengthen connections in response to experience.
Because a tendency to have seizures is one of the only behavioral symptoms in the mildly affected mice in the new study, seizures may be a primary deficit caused by excess MeCP2, the researchers say.
1: Bodda C. et al. Am. J. Pathol. 183, 195-210 (2013) PubMed