Investigating the homeostatic role of MeCP2 in mature brain

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DESCRIPTION (provided by applicant): Rett Syndrome (RTT) is a neurological disorder almost exclusively affecting females and caused by mutations in the X-linked gene MECP2, which encodes methyl-CpG binding protein 2 (MeCP2). Infants with RTT experience ostensibly normal development until 6-18 months of age but then regress, losing learned motor and language skills and progressively developing a broad range of additional neurological features over the course of their life. Whether MeCP2 function is required either to achieve and/or to maintain mature neurological function in the brain has remained historically unclear, but a recent study demonstrating how reexpression of Mecp2 in adult null mice can rescue features of disease has shifted the balance of evidence in favor of a "maintenance" role for MeCP2. An interesting unanswered question, however, is whether early expression of MeCP2 only through the critical period of early post-natal neurological development might alter the disease that evolves following later loss of the protein, suggesting a role for MeCP2 in development and neurological maturation that is independent of its role in maintenance. I hypothesize that there likely are developmental functions of MeCP2 and propose to test this by acutely deleting Mecp2 in adult mice using the tamoxifen inducible Cre/loxP system. I predict that since mice will become null after post-natal neurological development has been completed, mice will develop a RTT-like syndrome that recapitulates only those disease features related to maintenance functions that require MeCP2 while failing to recapitulate features related to developmental or maturational requirements of MeCP2, thus providing definitive conclusions about the two hypotheses of RTT. Mice will be characterized for general and behavioral phenotypes (using a battery of established mouse physiological and behavioral tests), neuropathological changes in the central nervous system, and gene transcriptional changes in a key brain region following adult induced knockout of Mecp2. Preliminary data confirms the efficacy of a novel tamoxifen dosing regimen devised by the applicant for 97% recombination of the Mecp2 allele in adult (post natal day 60) mice and behavioral pilot studies reveal distinct behavioral changes in adult induced null mice. The completed studies will address whether two phases of dysfunction contribute to RTT and whether post-natal developmental periods might be targeted to improve the outcomes of RTT patients. Furthermore, gene transcriptional changes may prioritize targeting of candidate genetic pathways for therapy. PUBLIC HEALTH RELEVANCE: The causes of autism - a major public health concern - are likely many and are not totally clear at this time, but the cause of Rett syndrome (RTT), a disease with many features of autism, is known to be mutations in the gene MECP2 almost every time. In the present study, this knowledge will be employed to study RTT in mice, giving us an inroad into the enigmatic mechanisms of autism, which is expected to teach us more about both how RTT and related disorders like autism occur and how to improve these patients' lives through new therapy.