Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome

Abstract

The postnatal neurodevelopmental disorder Rett syndrome, caused by mutations in MECP2, produces a diverse array of symptoms, including loss of language, motor, and social skills and the development of hand stereotypies, anxiety, tremor, ataxia, respiratory dysrhythmias, and seizures. Surprisingly, despite the diversity of these features, we have found that deleting Mecp2 only from GABAergic inhibitory neurons in mice replicates most of this phenotype. Here we show that genetically restoring Mecp2 expression only in GABAergic neurons of male Mecp2 null mice enhanced inhibitory signaling, extended lifespan, and rescued ataxia, apraxia, and social abnormalities but did not rescue tremor or anxiety. Female Mecp2 ^+/- mice showed a less dramatic but still substantial rescue. These findings highlight the critical regulatory role of GABAergic neurons in certain behaviors and suggest that modulating the excitatory/inhibitory balance through GABAergic neurons could prove a viable therapeutic option in Rett syndrome.

DOI: http://dx.doi.org/10.7554/eLife.14198.001

eLife digest

Rett syndrome is a childhood brain disorder that mainly affects girls and causes symptoms including anxiety, tremors, uncoordinated movements and breathing difficulties. Rett syndrome is caused by mutations in a gene called MECP2, which is found on the X chromosome. Males with MECP2 mutations are rare but have more severe symptoms and die young. Many researchers who study Rett syndrome use mice as a model of the disorder. In particular, male mice with the mouse equivalent of the human MECP2 gene switched off in every cell in the body (also known as Mecp2-null mice) show many of the features of Rett syndrome and die at a young age.

The MECP2 gene is important for healthy brain activity. The brain contains two major types of neurons: excitatory neurons, which encourage other neurons to be active; and inhibitory neurons, which stop or dampen the activity of other neurons. In 2010, researchers reported that mice lacking Mecp2 in only their inhibitory neurons develop most of the same problems as those mice with no Mecp2 at all. This discovery led Ure et al. – including a researcher involved in the 2010 study – to ask if activating Mecp2 in the same neurons in otherwise Mecp2-null mice was enough to prevent some of their Rett syndrome-like symptoms.

The experiments showed that male mice that only have Mecp2 activated in their inhibitory neurons lived several months longer than male Mecp2-null mice. These male “rescue mice” also moved normally and had a normal body weight, though they still experienced anxiety, tremors and breathing difficulties. Female mice represent a better model of human Rett syndrome patients, and Ure et al. found that female rescue mice showed smaller improvements than the males.

These data suggest that when a brain is missing Mecp2 everywhere, as in male Mecp2-null mice, turning on Mecp2 in inhibitory neurons can make the brain network nearly normal and prevent most Rett-syndrome-like symptoms. However, the brains of female rescue mice contain both normal cells and cells with mutated Mecp2. This mixture of normal and abnormal cells appears to cause abnormalities that cannot be overcome by rescuing just the activity of the inhibitory neurons. These findings also highlight the importance of doing future studies in female mice to better understand the development of Rett syndrome.

The next challenge is to test different ways of activating the inhibitory neurons in the female mouse brain, for example by using drugs that target these neurons. It is hoped these methods will help researchers to refine a path toward potential new treatments for Rett syndrome patients. Finally, in a related study, Meng et al. asked how deleting or activating Mecp2 only in the excitatory neurons of mice affected Rett-syndrome-like symptoms.

DOI: http://dx.doi.org/10.7554/eLife.14198.002