Haploinsufficiency of a Circadian Clock Gene Bmal1 (Arntl or Mop3) Causes Brain-Wide mTOR Hyperactivation and Autism-like Behavioral Phenotypes in Mice. Int J Mol Sci 2022 Jun 05;23(11)
Date
06/11/2022Pubmed ID
35682995Pubmed Central ID
PMC9181331DOI
10.3390/ijms23116317Scopus ID
2-s2.0-85131235233 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
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 Bmal1 (Arntl or Mop3) has been associated with human sociability, and its missense mutation is found in ASD. Our recent study found that Bmal1-null mice exhibit a variety of autism-like phenotypes. Here, we further investigated whether an incomplete loss of Bmal1 function could cause significant autism-like behavioral changes in mice. Our results demonstrated that heterozygous Bmal1 deletion (Bmal1+/-) 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, 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. The novel object recognition memory remained intact. Together, these results demonstrate that haploinsufficiency of Bmal1 can cause autism-like behavioral changes in mice, akin to those identified in Bmal1-null mice. This study provides further experimental evidence supporting a potential role for disrupted clock gene expression in the development of ASD.
Author List
Singla R, Mishra A, Lin H, Lorsung E, Le N, Tin S, Jin VX, Cao RAuthor
Victor X. Jin PhD Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ARNTL Transcription FactorsAnimals
Autistic Disorder
Brain
CLOCK Proteins
Circadian Clocks
Circadian Rhythm
Haploinsufficiency
Maternal Deprivation
Mice
Mice, Knockout
Phenotype
TOR Serine-Threonine Kinases
