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Rescue of Neuroanatomical Impairments Following Mecp2 Reactivation in Adult Mice
Objectives: We scanned mice longitudinally with MRI to determine: a) the brain regions affected by Mecp2 silencing and b) the spatial and temporal changes that occur in the brain following Mecp2 reactivation.
Methods: At P50, male Mecp2-STOP/Cre and Cre littermates were scanned in vivo with a Manganese-enhanced MRI protocol (MEMRI), followed by 4 weeks of treatment with oil or tamoxifen to reactivate Mecp2. At P80, a follow up MEMRI scan was conducted. The acquired images were aligned using a series of iterative linear and nonlinear registrations steps4. This process generates a consensus average representing each individual brain and the deformations of each image from this average. The Jacobian-determinants, which represents local volume changes, were then extracted from the deformations fields and used as the dependent variable in the statistical analyses to assess volumetric changes.
Results: At P50, Mecp2/Cre mice began to show reduced mobility and breathing impairments. At this age, total brain volume of Mecp2/Cre (n=9) mice was 14% smaller than Cre (n=5) controls (t-statistic=4.07, p < 0.001). Following normalization for brain volume, volumetric decreases were found across the cortex, striatum, hippocampus, while volumetric increases were found in the cerebellum and medulla. Following the baseline scan, Mecp2/Cre mice treated with oil showed a steady increase in body weight (beta=0.33, p < 0.05) and phenotypes reaching a score of 5 around 80 days of age. Conversely, tamoxifen treatment reduced the increase in body weight of Mecp2/Cre mice (beta=0.07, p=0.42) and reversed the increase in phenotype score from 2 at 60 days, to 0 by 80 days. At P80, the brain of Mecp2/Cre mice treated with tamoxifen (n=4) was 30% larger than Mecp2/Cre treated with oil (n=2) (t-statistic=8.71, p < 0.001). Interestingly, the tamoxifen treated Mecp2/Cre brain grew at a rate of 1.73mm3 per day (beta=1.73, p < 0.05), eventually reaching Cre control volumes at 80 days (t-statistic=0.32, p=0.76). A regional-based analysis demonstrated a lack of regional specificity, with all brain regions increasing in volume following Mecp2 reactivation.
Conclusions: Our results demonstrate that Mecp2 mice have volumetric differences across many brains networks early in adult life. However, following Mecp2 reactivation, a substantial neuroanatomical rescue occurs across the brain eventually normalizing with controls.
See more of: Brain Structure (MRI, neuropathology)