Methyl-CpG-binding protein 2 (MeCP2) is a multifunctional protein involved in neurogenesis, synaptogenesis, and activity-dependent gene expression in the brain. Mutations in the MECP2 gene are responsible for Rett Syndrome (RTT), a debilitating neurodevelopmental genetic disorder which primary affects females. While RTT mouse models have been extensively used, characterization of the molecular and gross brain features of mouse models recapitulating common MeCP2 mutations has yet to be fully established. Although there is no cure for RTT, several serious side effects have been reported associated with the use of trofinetide, a drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of RTT. Treatments for RTT through the repurposing of metabolic drugs such as the anti-diabetic drug, metformin, are promising alternative therapies with improvement of RTT symptoms as well as fewer/no side effects.

Anatomically, the gross brain weight and length of two specific MeCP2 mutations in mice were evaluated. The decreased brain weight and length observed in these RTT mouse models correspond with observations in the brain of RTT patients at the time of autopsy. Molecularly, MeCP2 protein expression levels were considerably reduced in specific brain regions of both RTT mouse models. Additionally, several synaptic markers, autophagy factors, and brain-derived neurotrophic factor (BDNF) protein levels were altered in the brain of both RTT mouse models. While metformin treatment in both RTT mouse models did not fully recover the reduced MeCP2 levels in the brain, some of the altered proteins were recovered to near wild type levels following metformin treatment. This study highlights a potential for repurposing of metformin in the context of RTT and, perhaps, other neurodevelopmental diseases.