20107
Loss of MeCP2 in the Rat Uniquely Models Regression, Impaired Sociability, and Transcriptional Deficits of Rett Syndrome

Saturday, May 16, 2015: 11:30 AM-1:30 PM
Imperial Ballroom (Grand America Hotel)
R. C. Samaco1,2, S. Veeraragavan1, S. M. Hamilton1, C. S. Ward2,3, S. Soriano1,2, Y. W. Wan2,4, M. R. Pitcher2,5, C. M. McGraw2,6,7, W. Yan1,2,8, J. R. Green1, L. Yuva1, A. J. Liang1,2, J. L. Neul2,3,9, D. H. Yasui10, J. M. LaSalle10,11, Z. Liu2,3 and R. Paylor1, (1)Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, (2)Jan and Dan Duncan Neurological Research Institute, Houston, TX, (3)Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX, (4)Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, (5)Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, (6)Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, (7)Neurology, University of California, San Francisco, San Francisco, CA, (8)Neurology, Xiangya Hospital, Central South University, Changsha, China, (9)Neurosciences, Division of Child Neurology, University of California, San Diego, San Diego, CA, (10)Medical Microbiology and Immunology, University of California, Davis, Davis, CA, (11)MIND Institute, Sacramento, CA
Background: Mouse models of the transcriptional modulator Methyl-CpG-Binding Protein 2 (MeCP2) have advanced our understanding of Rett syndrome (RTT). RTT is a ‘prototypical’ neurodevelopmental disorder with many clinical features overlapping with other IDD/ASD whose pathogenesis may be similar. Therapeutic interventions for RTT may therefore have broader applications. However, the reliance on the laboratory mouse may present challenges in translating findings from the bench to the clinic, and the need to identify outcome measures in well-chosen animal models is critical for preclinical trials.

Objectives: To identify disease-relevant neurobehavioral deficits that can be uniquely modeled in a rat model of Rett syndrome, and to compare transcriptional changes in MeCP2 rodent models and human Rett brain tissue.

Methods: Male Mecp2-/y and female Mecp2-/+ rats and their respective wild-type littermate controls were evaluated for anxiety-like behavior, motor function, sensorimotor gating and cognition at juvenile timepoints. Psychomotor regression and tests for sociability were performed with juvenile female Mecp2-/+ rats and wild-type littermate animals. RNA sequencing studies were conducted to examine the hypothalamic transcription profiles of male Mecp2-/y rats and wild-type littermate animals. Gene expression alterations were compared with previously published data to identify both common and unique transcriptional changes among MeCP2 rodent models. The predictive validity of common and unique transcriptional changes of MeCP2 rodents was assessed in human brain tissue from RTT and control individuals.

Results: A novel Mecp2 rat model displays psychomotor regression of a learned skill and impairments in juvenile play, two behavioral deficits that are unique to the rat model and that are highly relevant to RTT. In addition, the strategy of analyzing the loss of Mecp2 in both mouse and rat may result in higher predictive validity with respect to transcriptional changes in human RTT brain.

Conclusions: These data underscore the similarities and differences caused by the loss of MeCP2 among divergent rodent species which may have important implications for the treatment of individuals with disease-causing MECP2 mutations. Taken together, these findings demonstrate that the Mecp2 rat model is a complementary tool with unique features for the study of RTT and highlight the potential benefit of cross-species analyses in identifying potential disease-relevant preclinical outcome measures.

See more of: Animal Models
See more of: Animal Models