Altered cerebellar connectivity in autism and cerebellar-mediated rescue of autism-related behaviors in mice
Open accessAbstract
Cerebellar abnormalities, particularly in Right Crus I (RCrusI), are consistently reported in autism spectrum disorders (ASD). Although RCrusI is functionally connected with ASD-implicated circuits, the contribution of RCrusI dysfunction to ASD remains unclear. Here neuromodulation of RCrusI in neurotypical humans resulted in altered functional connectivity with the inferior parietal lobule, and children with ASD showed atypical functional connectivity in this circuit. Atypical RCrusI-inferior parietal lobule structural connectivity was also evident in the Purkinje neuron (PN) TscI ASD mouse model. Additionally, chemogenetically mediated inhibition of RCrusI PN activity in mice was sufficient to generate ASD-related social, repetitive, and restricted behaviors, while stimulation of RCrusI PNs rescued social impairment in the PN TscI ASD mouse model. Together, these studies reveal important roles for RCrusI in ASD-related behaviors. Further, the rescue of social behaviors in an ASD mouse model suggests that investigation of the therapeutic potential of cerebellar neuromodulation in ASD may be warranted.
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In mice, both congenital knockout and haploinsufficiency of Shank3 lead to diminished social interest in others and are associated with disruption of cortical and subcortical circuits thought to be involved in ASD and its ontogenesis.
“In mice, both congenital knockout and haploinsufficiency of Shank3 leads to diminished social interest in others and is associated with the disruption of cortical and subcortical circuits thought to be involved in ASD 22–26 and its ontogenesis 22,25,27,28.”
From Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time (2021) · cites this paper as [27]
ASD is known to involve other cortical-subcortical circuits.
“ASD is known to involve other cortical-subcortical circuits 27,36”
From Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time (2021) · cites this paper as [27]
Various neurophysiological features such as cortical volume and connectivity are also altered in ASD.
“various neurophysiological features such as cortical volume 35,47 and connectivity 27 are also altered in ASD.”
From Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time (2021) · cites this paper as [27]
Stimulation of Rcrus1 PC function rescues only social behaviors in PC-Tsc1 mutant mice.
“whereas stimulation of Rcrus1 PC function could rescue only social behaviors in PC-Tsc1 mutant mice.”
From Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits (2020) · cites this paper as [8]
Inhibition of Rcrus1 PCs generates both social impairments and repetitive behaviors in PC-Tsc1 mutant mice.
“We recently demonstrated that inhibition of Rcrus1 PCs could generate both social impairments and repetitive behaviors”
From Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits (2020) · cites this paper as [8]
Rcrus1 is functionally connected with the contralateral mPFC in humans.
“Rcrus1 is functionally connected with the contralateral mPFC in humans8,19”
From Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits (2020) · cites this paper as [8]
Connectivity exists between the left mPFC and Rcrus1 in humans and primates.
“We and others previously demonstrated connectivity between the left mPFC and Rcrus1 in humans and primates8,9,10.”
From Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits (2020) · cites this paper as [8]
Structural covariance mirrors findings of connectivity from functional or diffusion MRI studies.
“Structural covariance is a structural magnetic resonance imaging (MRI)-based technique that has been demonstrated to mirror findings of connectivity from functional or diffusion MRI studies8,25.”
From Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits (2020) · cites this paper as [8]
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 [8]
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References 91 · Cited by 387
- Authors
- Stoodley, C. J., D’Mello, A. M., Ellegood, J., Jakkamsetti, V., Liu, P., Nebel, M. B., Gibson, J. M., Kelly, E., Meng, F., Cano, C. A., Pascual, J. M., Mostofsky, S. H., Lerch, J. P., & Tsai, P. T.
- Affiliations
- American University (US)
- Hospital for Sick Children (CA)
- The University of Texas Southwestern Medical Center (US)
- Kennedy Krieger Institute (US)
- Corresponding author
- Stoodley, Catherine J.
- Tsai, Peter T.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2017-10-30
- Volume
- 20
- Issue
- 12
- Pages
- 1744-1751
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC5867894
- OpenAlex
- W2767035585
- Cited by
- 387
- References
- 91
- Citations by year
- 2026: 23 · 2025: 47 · 2024: 41 · 2023: 48 · 2022: 36 · 2021: 68 · 2020: 45 · 2019: 45 · 2018: 33 · 2016: 1
- FWCI
- 19.31
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-03-16)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH085328, R15MH106957, R01MH078160, K01MH109766)
- National Institute of Neurological Disorders and Stroke (K08NS083733, R01NS048527)
- 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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- autism spectrum disorder, cerebellum, Purkinje cells, inferior parietal lobule, functional connectivity, structural connectivity, social dysfunction, restricted and repetitive behaviors, chemogenetic inhibition, chemogenetic stimulation, cerebellar connectivity
- MeSH terms
- Autism Spectrum Disorder, Animals, Behavior, Animal, Cerebellum, Child, Female, Humans, Magnetic Resonance Imaging, Male, Mice, Transgenic, Neural Pathways, Purkinje Cells, Rest, Smell, Social Behavior, Maze Learning, Mice, Young Adult
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