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Rett Syndrome : Genes , Synapses , Circuits , and Therapeutics Citation

The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Development of the nervous system proceeds through a set of complex checkpoints which arise from a combination of sequential gene expression and early neural activity sculpted by the environment. Genetic and environmental insults lead to neurodevelopmental disorders which encompass a large group of diseases that result from anatomical and physiological abnormalities during maturation and development of brain circuits. Rett syndrome (RTT) is a neurological disorder of genetic origin, caused by mutations in the X-linked gene methyl-CpG binding protein 2 (MeCP2). It features a range of neuropsychiatric abnormalities including motor dysfunctions and mild to severe cognitive impairment. Here, we discuss key questions and recent studies describing animal models, cell-type specific functions of methyl-CpG binding protein 2 (MeCP2), defects in neural circuit plasticity, and attempts to evaluate possible therapeutic strategies for RTT. We also discuss how genes, proteins, and overlapping signaling pathways affect the molecular etiology of apparently unrelated neu-ropsychiatric disorders, an understanding of which can offer novel therapeutic strategies for a range of autism spectrum disorders (ASDs). INTRODUCTION Rett syndrome (RTT) [Online Mendelian Inheritance in Man (OMIM) #312750], first reported by the Austrian physician Andreas Rett, is a monogenic, postnatal developmental disorder that affects normal brain development during early childhood in females, with an incidence of 1 in 10,000–15,000 live births (Rett, 1966; Chahrour and Zoghbi, 2007). Patients with RTT appear to reach developmental milestones seemingly normally until about 6–18 months after birth when signs and symptoms of the disease begin to appear. mutations in the MECP2, which encodes a transcriptional regulator and epigenetic modifier MeCP2, have been found to be the primary genetic component in 90% of patients suffering from RTT Interestingly , only one copy of MECP2 is active in females due to random X-chromosome inactivation (Adler et al., 1995). RTT is not a heri-table disorder and most mutations in MECP2 arise de novo in germ cells, usually on the paternal side (Trappe et al., 2001). Growing evidence implicates alteration of MECP2 expression in the etiology of several other neuropsychiatric disorders including Angelman syndrome, childhood schizophrenia, and congenital encephalopa-thy in boys (Schule et al., 2008). Originally, RTT was considered to be a disorder of early postnatal life; however, one recent study has shown that inducible deletion of MECP2 in adults recapitulates the germ-line knock out phenotype in mice (McGraw et …