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Research Articles, Neurobiology of Disease

A Critical Period for Development of Cerebellar-Mediated Autism-Relevant Social Behavior

Jennifer M. Gibson, Cleone P. Howland, Chongyu Ren, Cyrena Howland, Alexandra Vernino and Peter T. Tsai
Journal of Neuroscience 30 March 2022, 42 (13) 2804-2823; DOI: https://doi.org/10.1523/JNEUROSCI.1230-21.2021
Jennifer M. Gibson
1Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390
2Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Cleone P. Howland
1Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Chongyu Ren
1Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Cyrena Howland
1Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Alexandra Vernino
1Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Peter T. Tsai
1Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390
2Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390
3Departments of Pediatrics and Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390
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Abstract

The cerebellum has been increasingly implicated in autism spectrum disorder (ASD) with many ASD-linked genes impacting both cerebellar function and development. However, the precise timing and critical periods of when abnormal cerebellar neurodevelopment contributes to ASD-relevant behaviors remains poorly understood. In this study, we identify a critical period for the development of ASD-relevant behaviors in a cerebellar male mouse model of tuberous sclerosis complex (TSC), by using the mechanistic target of rapamycin (mTOR) inhibitor, rapamycin, to pharmacologically inhibit dysregulated downstream signaling. We find independent critical periods during which abnormal ASD-relevant behaviors develop for the two core ASD diagnostic criteria, social impairments and behavioral flexibility, and delineate an anatomic, physiological, and behavioral framework. These findings not only further our understanding of the genetic mechanisms underlying the timing of ASD-relevant behaviors but also have the capacity to inform potential therapies to optimize treatment interventions.

SIGNIFICANCE STATEMENT No targeted treatments currently exist for autism spectrum disorder (ASD). This complex developmental disorder has established links to genetic and circuit aberrations, yet the precise timing and coordination of these underlying mechanisms that contribute to the spectrum of physiological and behavioral abnormalities remains unclear. Cerebellar pathology is consistently seen in ASD individuals; therefore, we sought to identify the specific windows for cerebellar involvement in the development of ASD-relevant behaviors. Using pharmacologic treatment paradigms, we outline distinct critical periods of developmental vulnerability for ASD-relevant social and inflexible behaviors. From this study, we posit a refined window of time during which ASD symptoms develop that will inform therapeutic timing.

  • autism
  • cerebellum
  • critical period
  • Purkinje cell
  • tuberous sclerosis

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The Journal of Neuroscience: 42 (13)
Journal of Neuroscience
Vol. 42, Issue 13
30 Mar 2022
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A Critical Period for Development of Cerebellar-Mediated Autism-Relevant Social Behavior
Jennifer M. Gibson, Cleone P. Howland, Chongyu Ren, Cyrena Howland, Alexandra Vernino, Peter T. Tsai
Journal of Neuroscience 30 March 2022, 42 (13) 2804-2823; DOI: 10.1523/JNEUROSCI.1230-21.2021

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A Critical Period for Development of Cerebellar-Mediated Autism-Relevant Social Behavior
Jennifer M. Gibson, Cleone P. Howland, Chongyu Ren, Cyrena Howland, Alexandra Vernino, Peter T. Tsai
Journal of Neuroscience 30 March 2022, 42 (13) 2804-2823; DOI: 10.1523/JNEUROSCI.1230-21.2021
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Keywords

  • autism
  • cerebellum
  • critical period
  • Purkinje cell
  • tuberous sclerosis

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