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

Rubal Singla, Abhishek Mishra, Hao Lin, Ethan Lorsung, Nam Le, Su Tin, Victor X. Jin, Ruifeng Cao

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
Article number6317
JournalInternational journal of molecular sciences
Issue number11
StatePublished - Jun 1 2022

Bibliographical note

Funding Information:
Funding: This research was partially funded by grants from the NIH (NS118026 and DK109714 to R.C. and GM114142 and CA217297 to V.X.J.).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.


  • autism
  • Bmal1
  • clock gene
  • mice
  • mTOR kinase

PubMed: MeSH publication types

  • Journal Article


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