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

Autor:	Gibson JM; Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390.; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390., Howland CP; Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Ren C; Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Howland C; Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Vernino A; Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Tsai PT; Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390 peter.tsai@utsouthwestern.edu.; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390.; Departments of Pediatrics and Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Jazyk:	angličtina
Zdroj:	The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2022 Mar 30; Vol. 42 (13), pp. 2804-2823. Date of Electronic Publication: 2022 Feb 21.
DOI:	10.1523/JNEUROSCI.1230-21.2021
Abstrakt:	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. (Copyright © 2022 the authors.)
Databáze:	MEDLINE
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