Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice
Open accessAbstract
Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology and correlate cerebellar pathology with increased ASD symptomatology. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.
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The altered vocal behavior suggests abnormal communication in Dock4 KO mice.
“This altered vocal behavior was reminiscent of some ASD mice models 33–35, suggesting abnormal communication in Dock4 KO mice.”
From Autism-like social deficit generated by Dock4 deficiency is rescued by restoration of Rac1 activity and NMDA receptor function. (2021) · cites this paper as [35]
Atypicalities in these brain regions are associated with autism, according to recent neuroimaging, postmortem, and animal-model studies.
“Indeed, the emerging picture from recent neuro-imaging, postmortem, and animal-model studies is that atypicalities in these regions are associated with autism (75 -80).”
From Autism as a disorder of prediction (2014) · cites this paper as [80]
Rapamycin successfully reduced cognitive impairment and social behavior deficit in mouse models of tuberous sclerosis and improved behavior in adult mice with a deletion of PTEN.
“Rapamycin successfully reduced cognitive impairment and social behavior deficit in mouse models of tuberous sclerosis 61-63 and improved behavior in adult mice with a deletion of PTEN 64 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [62]
Methods that can turn genes on or off in chosen cell types or brain areas now permit tracking autism-related behaviors at the cellular level.
“powerful new techniques that enable selective expression or deletion of genes in specific cell types or brain areas are enabling the tracing of ASD behaviors at the cellular level”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [356]
Previous reports implicating the cerebellum in the pathogenesis of social impairments in the Tsc1 KO model of ASD do not generalize across ASD.
“these results suggest that previous reports implicating the cerebellum in the pathogenesis of social impairments in the Tsc1 KO model of ASD (Kelly et al., 2020; Tsai et al., 2012) do not generalize across ASD”
From Parallel social information processing circuits are differentially impacted in autism (2020) · cites this paper as Tsai et al., 2012
PC-specific deletion of Tsc1 is sufficient to generate ASD-relevant social impairment and repetitive/inflexible behaviors in mice.
“PC-specific deletion of Tsc1 is sufficient to generate ASD-relevant social impairment and repetitive/inflexible behaviors in mice5.”
From Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits (2020) · cites this paper as [5]
Cerebellar output is negatively affected in ASD owing to significant PC loss and decreased cerebellar activity.
“This output is negatively affected in ASD owing to significant PC loss and decreased cerebellar activity2,5,42.”
From Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits (2020) · cites this paper as [5]
The sample size estimate was performed based on a repeated-measures ANOVA design (mixed-model ANOVA with covariance structure of compound symmetry) using PASS 12.
“The sample size estimate was performed based on a repeated-measures ANOVA design (mixed-model ANOVA with covariance structure of compound symmetry) using PASS 12 to estimate sample size5,8.”
From Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits (2020) · cites this paper as [5]
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Mapk/Erk activation in an animal model of social deficits shows a possible link to autism
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- Authors
- 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.
- Affiliations
- Boston Children's Hospital (US)
- Harvard University (US)
- National Institutes of Health (US)
- Corresponding author
- Tsai, Peter T.
- Venue
- Nature
- Published
- 2012-07-01
- Volume
- 488
- Issue
- 7413
- Pages
- 647-651
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3615424
- OpenAlex
- W2104582585
- Cited by
- 888
- References
- 40
- Citations by year
- 2026: 35 · 2025: 45 · 2024: 70 · 2023: 62 · 2022: 75 · 2021: 73 · 2020: 68 · 2019: 67 · 2018: 60 · 2017: 59 · 2016: 68 · 2015: 71 · 2014: 73 · 2013: 50 · 2012: 12
- FWCI
- 33.93
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of Mental Health (T32MH020017)
- National Institute of Neurological Disorders and Stroke (R01NS58956, R01NS058956, K12NS079414, R01NS032405, T32NS007473)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655, P30HD-18655)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, TSC1, tuberous sclerosis complex, Purkinje cells, cerebellum, mTOR signaling, rapamycin, social interaction deficits, repetitive behavior, neuronal stress, Purkinje cell degeneration
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Animals, Autistic Disorder, Behavior, Animal, Cell Count, Cerebellum, Grooming, Heterozygote, Mice, Inbred BALB C, Mice, Inbred C57BL, Mutation, Purkinje Cells, Synapses, Tuberous Sclerosis, Vocalization, Animal, Maze Learning, Sirolimus, Tumor Suppressor Proteins, Rotarod Performance Test, Cell Shape, Mice, TOR Serine-Threonine Kinases
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