Sensitive Periods for Cerebellar-Mediated Autistic-like Behaviors

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / drug therapy*
  • Autistic Disorder / etiology
  • Autistic Disorder / pathology
  • Behavior, Animal / drug effects*
  • Cells, Cultured
  • Cerebellum / drug effects*
  • Cerebellum / metabolism
  • Cerebellum / pathology
  • Immunosuppressive Agents / pharmacology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Purkinje Cells / drug effects
  • Purkinje Cells / metabolism
  • Purkinje Cells / pathology
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Tuberous Sclerosis Complex 1 Protein / physiology*

Substances

  • Immunosuppressive Agents
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Sirolimus