New paper linking Circadian Rhythms to ASD

Purkinje Cells (PC) in mouse cerebellum stained with antibodies against various proteins (Liu et al. 2022)

In collaboration with Ruifeng Cao's lab at UMN (https://med.umn.edu/bio/department-of-neuroscience/ruifeng-cao) we reveal a link between circadian clock dysregulation and Autism Spectrum Disorders (ASD) using mouse models.

Liu et al. Autistic-like behaviour and cerebellar dysfunction in Bmal1 mutant mice ameliorated by mTORC1 inhibition

Molecular Psychiatry DOI 10.1038/s41380-022-01499-6

This is the first study to provide evidence that cerebellar dysfunction downstream of the global deletion of an essential clock gene (Bmal1) in mice is linked to phenotypes reminiscent of ASD, which can be reversed with the antidiabetic drug metformin.

Deletion of Bmal1 only in PC cells of the cerebellum is sufficient to engender behavioural and cellular changes reminiscent of ASD. Our body’s Circadian Clock is an internal timing system that coordinates transcription and translation of gene networks that oscillate in a 24-h cycle, regulating physiology and behaviour. Bmal1 is an essential clock gene, as its deletion leads to complete loss of circadian rhythms in cells and mice. While a causal role for circadian clock dysfunction in Autism Spectrum Disorders (ASD) pathogenesis remains elusive, circadian and sleep problems are frequent ASD comorbidities.

Bmal1 and multiple clock genes were previously shown to harbour de novo loss-of-function mutations in ASD, while several clock genes are found in databases of ASD-associated genes.

Global Bmal1 deletion (KO) in mice led to complete loss of circadian rhythms together with significant social impairments, excessive stereotyped and repetitive behaviours & motor learning impairments, all of which resemble core behavioural alterations in ASD. Aberrant cell density and immature morphology of dendritic spines were identified in the cerebellar Purkinje cells (PCs) of Bmal1 KO mice, coupled with enhanced excitatory and inhibitory synaptic transmission and reduced firing rates.

Social behaviour analysis using the 3-chamber test in mice (Liu et al. 2022)

Using ribosome profiling and RNAseq, we identified differential gene-expression of ASD and ataxia-associated genes (Ntng2, Mfrp, Nr4a2, Thbs1, Atxn1, and Atxn3), altered translation of mRNAs and hyperactivation of mTORC1 pathway. Using the antidiabetic drug metformin, we reversed mTORC1 hyperactivation and alleviated major behavioral and PC deficits in Bmal1 KO mice.

Conditional Bmal1 deletion only in cerebellar PCs (using L7 promoter and Cre-Lox system) was sufficient to recapitulate behavioural and cellular changes reminiscent of ASD, akin to those identified in Bmal1 KO mice.

link to paper: https://rdcu.be/cJaaW