Autistic-like Behavior and Cerebellar Dysfunction in Bmal1 Mutant Mice Ameliorated by mTORC1 Inhibition
Open accessAbstract
Although circadian and sleep disorders are frequently associated with autism spectrum disorders (ASD), it remains elusive whether clock gene disruption can lead to autistic-like phenotypes in animals. The essential clock gene Bmal1 has been associated with human sociability and its missense mutations are identified in ASD. Here we report that global Bmal1 deletion led to significant social impairments, excessive stereotyped and repetitive behaviors, as well as motor learning disabilities in mice, all of which resemble core behavioral deficits in ASD. Furthermore, aberrant cell density and immature morphology of dendritic spines were identified in the cerebellar Purkinje cells (PCs) of Bmal1 knockout (KO) mice. Electrophysiological recordings uncovered enhanced excitatory and inhibitory synaptic transmission and reduced firing rates in the PCs of Bmal1 KO mice. Differential expression of ASD- and ataxia-associated genes (Ntng2, Mfrp, Nr4a2, Thbs1, Atxn1, and Atxn3) and dysregulated pathways of translational control, including hyperactivated mammalian target of rapamycin complex 1 (mTORC1) signaling, were identified in the cerebellum of Bmal1 KO mice. Interestingly, the antidiabetic drug metformin reversed mTORC1 hyperactivation and alleviated major behavioral and PC deficits in Bmal1 KO mice. Importantly, conditional Bmal1 deletion only in cerebellar PCs was sufficient to recapitulate autistic-like behavioral and cellular changes akin to those identified in Bmal1 KO mice. Together, these results unveil a previously unidentified role for Bmal1 disruption in cerebellar dysfunction and autistic-like behaviors. Our findings provide experimental evidence supporting a putative role for dysregulation of circadian clock gene expression in the pathogenesis of ASD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The association between toe walking and sleep disturbances corroborates the notion that motor dysregulation and sleep alterations may share underlying neurobiological mechanisms in ASD.
“This association corroborates the notion that motor dysregulation and sleep alterations may share underlying neurobiological mechanisms in ASD [40].”
From The Prevalence and Clinical Significance of Toe Walking in Autism Spectrum Disorder: A Cross-Sectional Study in an Italian Pediatric Sample (2025) · cites this paper as [40]
The Introduction identifies sleep problems as common in ASD, and the Results report motor-coordination deficits in mice lacking the circadian clock gene Bmal1. These findings are consistent with a possible shared mechanism, but the paper does not test sleep disturbances alongside motor deficits or examine toe walking. The cited evidence therefore does not establish the proposed link in people with ASD. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The contribution of de novo coding mutations to autism spectrum disorder
Iossifov, I., O’Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., Stessman, H. A., Witherspoon, K. T., Vives, L., Patterson, K. E., et al. (2014) · Nature · doi:10.1038/nature13908 · Cited by 2,585 · see citing works
Lai, M.-C., Lombardo, M. V., & Baron-Cohen, S. (2014) · The Lancet · doi:10.1016/s0140-6736(13)61539-1 · Cited by 2,371 · see citing works
Mop3 is an essential component of the master circadian pacemaker in mammals.
Bunger, M. K., Wilsbacher, L. D., Moran, S. M., Clendenin, C., Radcliffe, L. A., Hogenesch, J. B., Simon, M. C., Takahashi, J. S., & Bradfield, C. A. (2000) · Cell · doi:10.1016/s0092-8674(00)00205-1 · Cited by 1,621 · see citing works
The genetics of mammalian circadian order and disorder: implications for physiology and disease
Takahashi, J. S., Hong, H.-K., Ko, C. H., & McDearmon, E. L. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2430 · Cited by 1,611 · see citing works
Kondratov, R. V., Kondratova, A. A., Gorbacheva, V. Y., Vykhovanets, O. V., & Antoch, M. P. (2006) · Genes & Development · doi:10.1101/gad.1432206 · Cited by 1,188 · see citing works
Dentritic spines : structure, dynamics and regulation
Hering, H., & Sheng, M. (2001) · Nature Reviews Neuroscience · doi:10.1038/35104061 · Cited by 961 · see citing works
Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice
Tsai, P. T., Hull, C., Chu, Y., Greene-Colozzi, E., Sadowski, A. R., Leech, J. M., Steinberg, J., Crawley, J. N., Regehr, W. G., & Sahin, M. (2012) · Nature · doi:10.1038/nature11310 · Cited by 888 · see citing works
SFARI Gene 2.0: a community-driven knowledgebase for the autism spectrum disorders (ASDs)
Abrahams, B. S., Arking, D. E., Campbell, D. B., Mefford, H. C., Morrow, E. M., Weiss, L. A., Menashe, I., Wadkins, T., Banerjee-Basu, S., & Packer, A. (2013) · Molecular Autism · doi:10.1186/2040-2392-4-36 · Cited by 873 · see citing works
The Cerebellum, Sensitive Periods, and Autism
Wang, S. S. ‐., Kloth, A. D., & Badura, A. (2014) · Neuron · doi:10.1016/j.neuron.2014.07.016 · Cited by 829 · see citing works
Lipton, J. O., & Şahin, M. (2014) · Neuron · doi:10.1016/j.neuron.2014.09.034 · Cited by 732 · see citing works
The Autistic Neuron: Troubled Translation?
Kelleher, R. J., & Bear, M. F. (2008) · Cell · doi:10.1016/j.cell.2008.10.017 · Cited by 598 · see citing works
Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration
Musiek, E. S., Lim, M. M., Yang, G., Bauer, A. Q., Qi, L., Lee, Y., Roh, J. H., Ortiz-Gonzalez, X., Dearborn, J. T., Culver, J. P., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci70317 · Cited by 524 · see citing works
Autism-related deficits via dysregulated eIF4E-dependent translational control
Gkogkas, C. G., Khoutorsky, A., Ran, I., Rampakakis, E., Nevarko, T., Weatherill, D. B., Vasuta, C., Yee, S., Truitt, M., Dallaire, P., et al. (2013) · Nature · doi:10.1038/nature11628 · Cited by 522 · see citing works
Self-citationDyspraxia in autism: association with motor, social, and communicative deficits
Dziuk, M., Larson, J. C. G., Apostu, A., Mahone, E. M., DENCKLA, M. B., & Mostofsky, S. H. (2007) · Developmental Medicine & Child Neurology · doi:10.1111/j.1469-8749.2007.00734.x · Cited by 466 · see citing works
Spatiotemporal firing patterns in the cerebellum
Zeeuw, C. I. D., Hoebeek, F. E., Bosman, L. W. J., Schonewille, M., Witter, L., & Koekkoek, S. K. E. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn3011 · Cited by 411 · see citing works
Exaggerated translation causes synaptic and behavioural aberrations associated with autism
Santini, E., Huynh, T. N., MacAskill, A. F., Carter, A. G., Pierre, P., Ruggero, D., Kaphzan, H., & Klann, E. (2012) · Nature · doi:10.1038/nature11782 · Cited by 376 · see citing works
The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation
Lipton, J. O., Yuan, E. D., Boyle, L. M., Ebrahimi‐Fakhari, D., Kwiatkowski, E. R., Nathan, A., Guettler, T., Davis, F. C., Asara, J. M., & Şahin, M. (2015) · Cell · doi:10.1016/j.cell.2015.04.002 · Cited by 335 · see citing works
Cerebellar modules operate at different frequencies
Zhou, H., Lin, Z., Voges, K., Ju, C., Gao, Z., Bosman, L. W. J., Ruigrok, T. J. H., Hoebeek, F. E., Zeeuw, C. I. D., & Schonewille, M. (2014) · eLife · doi:10.7554/elife.02536 · Cited by 335 · see citing works
Bhattacharya, A., Kaphzan, H., Alvarez-Dieppa, A. C., Murphy, J. P., Pierre, P., & Klann, E. (2012) · Neuron · doi:10.1016/j.neuron.2012.07.022 · Cited by 316 · see citing works
Local and long-range functional connectivity is reduced in concert in autism spectrum disorders
Khan, S., Gramfort, A., Shetty, N. R., Kitzbichler, M. G., Ganesan, S., Moran, J. M., Lee, S. M., Gabrieli, J. D. E., Tager-Flusberg, H. B., Joseph, R. M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1214533110 · Cited by 303 · see citing works
Herzog, E. D., Hermanstyne, T. O., Smyllie, N. J., & Hastings, M. H. (2017) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a027706 · Cited by 268 · see citing works
Laurence, J. A., & Fatemi, S. H. (2005) · The Cerebellum · doi:10.1080/14734220500208846 · Cited by 246 · see citing works
The Implications of Multiple Circadian Clock Origins
Rosbash, M. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000062 · Cited by 239 · see citing works
Metformin ameliorates core deficits in a mouse model of fragile X syndrome
Gantois, I., Khoutorsky, A., Popić, J., Aguilar‐Valles, A., Freemantle, E., Cao, R., Sharma, V. K., Pooters, T., Nagpal, A., Skalecka, A., et al. (2017) · Nature Medicine · doi:10.1038/nm.4335 · Cited by 228 · see citing works
Self-citationmTOR signaling regulates central and peripheral circadian clock function
Ramanathan, C., Kathale, N. D., Liu, D., Lee, C., Freeman, D. A., Hogenesch, J. B., Cao, R., & Liu, A. C. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007369 · Cited by 206 · see citing works
Self-citationGkogkas, C. G., Khoutorsky, A., Cao, R., Jafarnejad, S. M., Prager-Khoutorsky, M., Giannakas, N., Kaminari, A., Fragkouli, A., Nader, K., Price, T. J., et al. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.064 · Cited by 201 · see citing works
Self-citationNicholas, B., Rudrasingham, V., Nash, S., Kirov, G., Owen, M. J., & Wimpory, D. C. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4001953 · Cited by 170 · see citing works
Cao, R., Robinson, B., Xu, H., Gkogkas, C. G., Khoutorsky, A., Alain, T., Yanagiya, A., Nevarko, T., Liu, A. C., Amir, S., et al. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.026 · Cited by 143 · see citing works
Self-citationMetformin as targeted treatment in fragile X syndrome
Dy, A. B. C., Tassone, F., Eldeeb, M., Salcedo‐Arellano, M. J., Tartaglia, N., & Hagerman, R. (2018) · Clinical Genetics · doi:10.1111/cge.13039 · Cited by 124 · see citing works
Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients
Yang, Z., Matsumoto, A., Nakayama, K., Jimbo, E. F., Kojima, K., Nagata, K., Iwamoto, S., & Yamagata, T. (2015) · Brain and Development · doi:10.1016/j.braindev.2015.04.006 · Cited by 121 · see citing works
Impaired Glucocorticoid Production and Response to Stress in Arntl-Deficient Male Mice
Leliavski, A., Shostak, A., Husse, J., & Oster, H. (2013) · Endocrinology · doi:10.1210/en.2013-1531 · Cited by 120 · see citing works
Genetic disruption of the core circadian clock impairs hippocampus-dependent memoryPreprint
Wardlaw, S. M., Phan, T., Saraf, A., Chen, X., & Storm, D. R. (2014) · Learning & Memory · doi:10.1101/lm.035451.114 · Cited by 113 · see citing works
Monyak, R. E., Emerson, D., Schoenfeld, B. P., Zheng, X., Chambers, D. B., Rosenfelt, C., Langer, S., Hinchey, P., Choi, C. H., McDonald, T. V., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2016.51 · Cited by 100 · see citing works
The Neuropathology of the Autism Spectrum Disorders: What Have We Learned?
Bauman, M. L., & Kemper, T. L. (2003) · Novartis Foundation symposium · doi:10.1002/0470869380.ch8 · Cited by 95 · see citing works
Price, K. H., Dziema, H., Aten, S., Loeser, J., Norona, F. E., Hoyt, K. R., & Obrietan, K. H. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.04.027 · Cited by 94 · see citing works
Circadian regulation of mTOR signaling in the mouse SCN
Cao, R., Anderson, F. E., Jung, Y.-J., Dziema, H., & Obrietan, K. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.03.005 · Cited by 84 · see citing works
Self-citationLight-regulated translational control of circadian behavior by eIF4E phosphorylation
Cao, R., Gkogkas, C. G., de Zavalía, N., Blum, I. D., Yanagiya, A., Tsukumo, Y., Xu, H., Lee, C., Storch, K.-F., Liu, A. C., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4010 · Cited by 83 · see citing works
Self-citationLoss of eIF4E Phosphorylation Engenders Depression-like Behaviors via Selective mRNA Translation
Amorim, I. S., Kedia, S., Kouloulia, S., Simbriger, K., Gantois, I., Jafarnejad, S. M., Li, Y., Kampaite, A., Pooters, T., Romanò, N., et al. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.2673-17.2018 · Cited by 82 · see citing works
Self-citationYang, Y., Arsenault, J., Bah, A., Krzeminski, M., Fekete, Á., Chao, O. Y.-H., Pacey, L. K. K., Wang, A. B., Forman-Kay, J. D., Hampson, D. R., et al. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0240-0 · Cited by 70 · see citing works
Metformin treatment in young children with fragile X syndrome
Biag, H. M. B., Potter, L. A., Wilkins, V., Afzal, S., Rosvall, A., Salcedo‐Arellano, M. J., Rajaratnam, A., Manzano‐Nunez, R., Schneider, A., Tassone, F., et al. (2019) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.956 · Cited by 68 · see citing works
Whitney, E. R., Kemper, T. L., Rosene, D. L., Bauman, M. L., & Blatt, G. J. (2007) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2007.09.009 · Cited by 65 · see citing works
Lorsung, E., Ramanujam, K., & Cao, R. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.642745 · Cited by 63 · see citing works
Self-citationGenetic underpinnings of sociability in the general population
Bralten, J., Mota, N. R., Klemann, C. J. H. M., Witte, W. D., Laing, E., Collier, D. A., de Kluiver, H., Bauduin, S., Arango, C., Ayuso‐Mateos, J. L., et al. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-01044-z · Cited by 59 · see citing works
Neurogenetic disorders across the lifespan: from aberrant development to degeneration
Hickman, R. A., O’Shea, S. A., Mehler, M. F., & Chung, W. K. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-021-00595-5 · Cited by 55 · see citing works
Kawamura, Y., Nakayama, H., Hashimoto, K., et al. (2013) · Nature Communications · doi:10.1038/ncomms3732 · Cited by 49 · see citing works
Crawford, J. D., Chandley, M., Szebeni, K., Szebeni, A., Waters, B., & Ordway, G. A. (2015) · Autism Research · doi:10.1002/aur.1480 · Cited by 43 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- [5]5. Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet 2014; 383(9920): 896– 910. 24074734
- [42]42. Cao R, Anderson FE, Jung YJ, Dziema H, Obrietan K. Circadian regulation of mammalian target of rapamycin signaling in the mouse suprachiasmatic nucleus. Neuroscience 2011; 181: 79– 88. 21382453 PMC3102430
Cited by
Sorted by citations
Costanza, C., Gallai, B., Sorrentino, M., Gnazzo, M., Pisanò, G., Parisi, L., Germanò, E., Maltese, A., Esposito, M., Roccella, M., et al. (2025) · Medicina · doi:10.3390/medicina61081346 · Cited by 5 · see citing works
- Authors
- Liu, D., Nanclares, C., Simbriger, K., Fang, K., Lorsung, E., Le, N., Amorim, I. S., Chalkiadaki, K., Pathak, S. S., Li, J., Gewirtz, J. C., Jin, V. X., Kofuji, P., Araque, A., Orr, H. T., Gkogkas, C. G., & Cao, R.
- Affiliations
- University of Minnesota (US)
- Simons Initiative for the Developing Brain (GB)
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Gkogkas, Christos G.
- Cao, Ruifeng
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2022-03-17
- Volume
- 28
- Issue
- 9
- Pages
- 3727-3738
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC9481983
- OpenAlex
- W4220752416
- Cited by
- 56
- References
- 46
- Citations by year
- 2026: 4 · 2025: 17 · 2024: 11 · 2023: 15 · 2022: 9
- FWCI
- 6.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (118026)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Keywords
- Bmal1, autism spectrum disorder, clock genes, Purkinje cells, mTORC1 signaling, metformin, social dysfunction, motor learning, dendritic spines, synaptic transmission, translational regulation, conditional knockout mice
- MeSH terms
- Autism Spectrum Disorder, Mechanistic Target of Rapamycin Complex 1, Social Interaction, Animals, Autistic Disorder, Cerebellar Diseases, Cerebellum, Electrophysiology, Humans, Learning, Mammals, Metformin, Mice, Inbred C57BL, Purkinje Cells, Stereotyped Behavior, Protein Biosynthesis, Mice, Knockout, Mice, ARNTL Transcription Factors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
