Mutations in the X-linked gene that encodes MeCP2 (MECP2) cause Rett Syndrome (RTT) in girls and severe congenital encephalopathy in boys. Although cognitive impairment and neurological dysfunction are hallmarks of these disorders, affected individuals also have disruption of many autonomic functions. Girls with RTT have highly irregular breathing and abnormalities in cardiac rhythm including prolonged corrected QT interval and decreased beat-to-beat variability. One quarter of deaths in RTT are sudden and unexpected; autonomic abnormalities are believed to underlie their deaths. Boys with mutations in MECP2 and congenital encephalopathy have a number of autonomic abnormalities including bradycardia, apnea, and respiratory arrest resulting in death in the first three years of life. Male mice lacking MeCP2 function (Mecp2null/Y) have shortened lifespan and reproduce many clinical features of RTT including autonomic changes such as breathing abnormalities and long QTc. However, the relationship between the physiological changes observed during the progression towards death remains unknown. We have recently discovered that removing MeCP2 function from distinct anatomical regions can reproduce the premature death seen in Mecp2null/Y animals. These findings lead to the hypothesis that loss of MeCP2 function within specific neuronal populations leads to premature death secondary to autonomic dysfunction. The goal of this work is to determine the physiological changes that precede and lead to death and to identify key anatomical regions in which loss of MeCP2 leads to autonomic dysfunction and death. The specific aims are: 1) Determine the physiological changes in Mecp2null/Y animals. Understanding the temporal relationship of various physiological changes will provide insight into the primary cause of death. 2) Define critical anatomical regions that require MeCP2 function for normal lifespan and physiology using a conditional knock-out approach. This will determine anatomical regions in which MeCP2 function is required for autonomic control; furthermore, elucidation of specific physiological abnormalities that precede or lead to premature death will suggest causality. 3) Identify anatomical regions in which restoring MeCP2 function is able to rescue premature death and improve physiology. The information obtained from this project will work towards an understanding of the underlying causes of death and autonomic dysfunction in humans with MECP2 related disorders. In addition, it will further the understanding and definition of neuronal circuits that control key autonomic functions. This knowledge will not only be useful in developing therapies for RTT and other MECP2 related disorders but will also provide mechanistic understanding that might give insight into other clinical disorders that have alterations in respiration, cardiac function, or autonomic control, such as sudden infant death, congenital hypoventilation syndrome, familial dysautonomia, and multiple system atrophy.