Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism

Neuropsychopharmacology. 2014 Mar;39(4):831-40. doi: 10.1038/npp.2013.274. Epub 2013 Oct 7.


Autism spectrum disorders (ASD) are defined by behavioral deficits in social interaction and communication, repetitive stereotyped behaviors, and restricted interests/cognitive rigidity. Recent studies in humans and animal-models suggest that dysfunction of the cholinergic system may underlie autism-related behavioral symptoms. Here we tested the hypothesis that augmentation of acetylcholine (ACh) in the synaptic cleft by inhibiting acetylcholinesterase may ameliorate autistic phenotypes. We first administered the acetylcholinesterase inhibitor (AChEI) Donepezil systemically by intraperitoneal (i.p.) injections. Second, the drug was injected directly into the rodent homolog of the caudate nucleus, the dorsomedial striatum (DMS), of the inbred mouse strain BTBR T+tf/J (BTBR), a commonly-used model presenting all core autism-related phenotypes and expressing low brain ACh levels. We found that i.p. injection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner. Microinjection of the drug directly into the DMS, but not into the ventromedial striatum, led to significant amelioration of the cognitive-rigidity and social-deficiency phenotypes. Taken together, these findings provide evidence of the key role of the cholinergic system and the DMS in the etiology of ASD, and suggest that elevated cognitive flexibility may result in enhanced social attention. The potential therapeutic effect of AChEIs in ASD patients is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism*
  • Animals
  • Autistic Disorder / complications*
  • Autistic Disorder / genetics
  • Caudate Nucleus / drug effects
  • Caudate Nucleus / physiology
  • Cholinesterase Inhibitors / therapeutic use
  • Cognition Disorders / drug therapy
  • Cognition Disorders / etiology*
  • Cognition Disorders / metabolism*
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiology
  • Disease Models, Animal
  • Donepezil
  • Drug Administration Routes
  • Exploratory Behavior / drug effects
  • Indans / therapeutic use
  • Interpersonal Relations
  • Locomotion / drug effects
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred Strains
  • Piperidines / therapeutic use
  • Social Behavior Disorders / drug therapy
  • Social Behavior Disorders / etiology*
  • Social Behavior Disorders / metabolism*
  • Stereotyped Behavior


  • Cholinesterase Inhibitors
  • Indans
  • Piperidines
  • Donepezil
  • Acetylcholine