Haploinsufficiency of a Circadian Clock Gene Bmal1 ( Arntl or Mop3 ) Causes Brain-Wide mTOR Hyperactivation and Autism-like Behavioral Phenotypes in Mice

• Published in: International journal of molecular sciences 2022-06, Vol.23 (11), p.6317
• Main Authors: Singla, Rubal, Mishra, Abhishek, Lin, Hao, Lorsung, Ethan, Le, Nam, Tin, Su, Jin, Victor X, Cao, Ruifeng
• Format: Article
• Language: English
• Subjects: Animals; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Autism; Autistic Disorder - genetics; Behavior; Biological clocks; BMAL1 protein; Brain; Brain - metabolism; Circadian Clocks - genetics; Circadian rhythm; Circadian Rhythm - genetics; Circadian rhythms; Clock gene; CLOCK Proteins - genetics; Communication; Gene expression; Haploinsufficiency; Labeling; Maternal Deprivation; Mice; Mice, Knockout; Missense mutation; Mutation; Pattern recognition; Period 1 protein; Period 2 protein; Phenotype; Phenotypes; Preferences; Proteins; Rodents; Sleep; Sleep disorders; Social behavior; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23116317

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. The essential clock gene ( or ) has been associated with human sociability, and its missense mutation is found in ASD. Our recent study found that -null mice exhibit a variety of autism-like phenotypes. Here, we further investigated whether an incomplete loss of function could cause significant autism-like behavioral changes in mice. Our results demonstrated that heterozygous deletion ( ) reduced the Bmal1 protein levels by ~50-75%. Reduced Bmal1 expression led to decreased levels of clock proteins, including Per1, Per2, Cry 1, and Clock but increased mTOR activities in the brain. Accordingly, 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. The novel object recognition memory remained intact. Together, these results demonstrate that haploinsufficiency of can cause autism-like behavioral changes in mice, akin to those identified in -null mice. This study provides further experimental evidence supporting a potential role for disrupted clock gene expression in the development of ASD.