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Cell Rep. 2018 Oct 9;25(2):357-367.e4. doi: 10.1016/j.celrep.2018.09.039.

Sensitive Periods for Cerebellar-Mediated Autistic-like Behaviors.

Author information

1
F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA. Electronic address: peter.tsai@utsouthwestern.edu.
2
Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
3
Mouse Imaging Centre, Hospital for Sick Kids, Toronto, ON, Canada.
4
Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX, USA.
5
F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
6
Mouse Imaging Centre, Hospital for Sick Kids, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
7
F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: mustafa.sahin@childrens.harvard.edu.

Abstract

Despite a prevalence exceeding 1%, mechanisms underlying autism spectrum disorders (ASDs) are poorly understood, and targeted therapies and guiding parameters are urgently needed. We recently demonstrated that cerebellar dysfunction is sufficient to generate autistic-like behaviors in a mouse model of tuberous sclerosis complex (TSC). Here, using the mechanistic target of rapamycin (mTOR)-specific inhibitor rapamycin, we define distinct sensitive periods for treatment of autistic-like behaviors with sensitive periods extending into adulthood for social behaviors. We identify cellular and electrophysiological parameters that may contribute to behavioral rescue, with rescue of Purkinje cell survival and excitability corresponding to social behavioral rescue. In addition, using anatomic and diffusion-based MRI, we identify structural changes in cerebellar domains implicated in ASD that correlate with sensitive periods of specific autism-like behaviors. These findings thus not only define treatment parameters into adulthood, but also support a mechanistic basis for the targeted rescue of autism-related behaviors.

KEYWORDS:

Purkinje cell; autism; cerebellum; sensitive periods; treatment; tuberous sclerosis

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