Note that the p-S6 levels were increased in all cerebellar lobules in the Bmal1 +/− mice as compared to the WT mice. N = 15 sections from 3 mice of each genotype.
Left: Representative bright field microscopic images of sagittal mouse cerebellar sections immunolabeled for phospho-S6 as an indicator of mTOR activities. ( C) mTOR hyperactivation in the cerebellum of Bmal1 +/− mice. Cell nuclei were counterstained by DAP1 (blue). ( B) Confocal microscopic images of mouse cerebellar sections immunolabeled for phospho-S6 (p-S6, green) and Calbindin-D (28k) (red). Bottom: Bar graphs indicate the quantification of Bmal1 protein levels (left) (cerebellum: t (6) = 5.279, p = 0.0019 forebrain: t (6) = 9.553, p < 0.0001, Student’s t-test) and phospho-S6 protein levels (right) (cerebellum: t (6) = 2.455, p = 0.0495 forebrain: t (6) = 2.619, p = 0.0396, Student’s t-test). Top: Representative Western blots indicating decreased Bmal1 protein levels and increased phospho-S6 levels in the cerebellum (left) and forebrain (right) of the Bmal1 +/− mice. ( A) Haploinsufficiency of Bmal1 expression and brain-wide mTOR hyperactivation in Bmal1 +/− mice. Heterozygous Bmal1 mutation leads to decreased Bmal1 expression and increased mTOR activation in the mouse brain. This study provides further experimental evidence supporting a potential role for disrupted clock gene expression in the development of ASD.īmal1 autism clock gene mTOR kinase mice. Together, these results demonstrate that haploinsufficiency of Bmal1 can cause autism-like behavioral changes in mice, akin to those identified in Bmal1-null mice. The novel object recognition memory remained intact. Accordingly, Bmal1 +/- mice exhibited aberrant ultrasonic vocalizations during maternal separation, deficits in sociability and social novelty, excessive repetitive behaviors, impairments in motor coordination, as well as increased anxiety-like behavior. Reduced Bmal1 expression led to decreased levels of clock proteins, including Per1, Per2, Cry 1, and Clock but increased mTOR activities in the brain. Our results demonstrated that heterozygous Bmal1 deletion ( Bmal1 +/-) reduced the Bmal1 protein levels by ~50-75%.
Here, we further investigated whether an incomplete loss of Bmal1 function could cause significant autism-like behavioral changes in mice. Our recent study found that Bmal1-null mice exhibit a variety of autism-like phenotypes. The essential clock gene Bmal1 ( Arntl or Mop3) has been associated with human sociability, and its missense mutation is found in ASD. Approximately 50-80% of children with autism spectrum disorders (ASDs) exhibit sleep problems, but the contribution of circadian clock dysfunction to the development of ASDs remains largely unknown.
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