NEUROBIOLOGY OF RETT’S SYNDROME: CELLULAR ETIOLOGY AND EXPERIMENTAL THERAPEUTIC STRATEGIES IN AN ANIMAL MODEL

Rett syndrome is a leading cause of mental retardation, second only to Down syndrome, which affects almost exclusively girls. This disease becomes manifest after a period of apparently normal development and causes growth retardation, severe psychomotor impairment and autistic behaviour. The majority of cases of Rett syndrome are caused by mutations in the gene encoding MECP2, a protein which binds DNA and regulates the expression of other genes, including that of brain-derived neurotrophic factor (BDNF), a major neurotrophin involved in brain development. Although many different mutations of the MECP2 protein are being studied in humans and in animal models, the molecular deficits which lead to the disease are presently unknown. Using a mouse model which carries a mutation in the MECP2 gene and mimics human Rett syndrome, we will study the molecular basis of this disorder, to understand how it affects neuronal circuitry and function. In particular, we will investigate whether inhibitory circuits and BDNF levels are altered in the brains of MECP2 deficient mice, and whether this leads to alterations of neuronal development, maturation and function. In addition, we will try rescue experiments using a behavioural therapy and reestablishing physiological levels of BDNF, that could help in the development of a therapy. Elucidating the cascade of events that results from disruption of MECP2 function is an essential step toward understanding the pathogenesis of Rett syndrome, and may be of value for the treatment of this devastating disorder.