Rett Syndrome is a neurodevelopmental disorder that primarily affects girls during early childhood. These individuals are born asymptomatic and develop normally until 6-18 months of age when a variety of symptoms appear gradually such as weight loss, ataxia and gait apraxia, loss of motor coordination, changes in social behavior and autonomic anomalies such as breathing and cardiac perturbations. The majority of Rett Syndrome cases are caused by sporadic mutations in the X-linked gene MECP2, a transcriptional modulator with a great variety of gene targets. One of the best known targets is BDNF, known to trigger neuronal and synaptic maturation through activation of signaling pathways such as PI3K/Akt. In fact studies in mouse models of Rett Syndrome have demonstrated the therapeutic effects of activating the PI3K/Akt pathway with BDNF or a common activator, IGF1. Unlike BDNF, IGF1 is able to cross the blood brain barrier and daily injections of a tri-peptide form of IGF1 is able to partially reverse many of the symptoms (Tropea et al., PNAS 106: 2029, 2009). In this study we have tested the therapeutic effects of recombinant human IGF1 (rhIGF1) in a mouse model of Rett syndrome. This full length, 70 amino acid version of IGF1 is expected to be more effective and holds significant potential as a clinical treatment. Beginning at 2 weeks of age, MeCP2 null mice and wild type littermates were injected daily with rhIGF1 throughout their lifetime. Treated animals showed significant increase in lifespan and improvement in body weight as compared to saline treated MeCP2 null mice. These effects in the treated group were accompanied by the improvement of locomotion at 8 weeks and recovery of cardiac and respiratory rhythms to those of wild type levels. In a social preference test measured by a three-chamber assay, wild type mice showed significant habituation in their social interactions, as demonstrated by reduced interactions with a stimulus mouse on a second encounter. MeCP2 null mouse showed no such habituation in their social interactions, whereas treatment with rhIGF1 restored habituation to wild type levels. These data demonstrate recovery of function at organismal and brain system levels in MeCP2 null mice due to rhIGF1 treatment, and point to widespread impact of IGF1 signaling in this disorder. They are consistent with the hypothesis that deficits in signaling pathways that influence synapse maturation are a key component of MeCP2 dysfunction or deletion, and suggest that rhIGF1 is a potential therapeutic for Rett Syndrome.

Society for Neuroscience Abstract, 2011.