Vitamin A deficiency exacerbates autism-like behaviors and abnormalities of the enteric nervous system in a valproic acid-induced rat model of autism

Neurotoxicology. 2020 Jul:79:184-190. doi: 10.1016/j.neuro.2020.06.004. Epub 2020 Jun 8.

Abstract

The manifestations of autism spectrum disorder (ASD) are highly heterogeneous. As many individuals with ASD have gastrointestinal (GI) comorbidities, ASD with GI problems is considered to be a subtype of ASD. Vitamin A (VA) plays an important role in the development of both the central and peripheral nervous system. However, the relationship between VA deficiency (VAD) and ASD with GI comorbidities is still unclear. We established rat models with different VA levels based on the valproic acid-induced autism model. Compared to autism model rats with VA normal (VAN), autism model rats with gestational VAD showed more severe autism-like behavior, increased GI transit time, and impairment of the enteric nervous system (ENS). Besides, the expression levels of retinoic acid receptor α (RARα) and Ret in autism model rats with VAD were decreased compared with those in rats with VAN. Supplementation with VA was found to effectively ameliorate autism-like behaviors and impairments of GI motility and the ENS in autism model rats with VAD. Chromatin immunoprecipitation results suggested that RARa can bind to the promoter region of the Ret gene and regulate the Ret signaling pathway. We speculate that VAD in autism might lead to impairments of both the brain and ENS. VAD might be a factor that causes individuals to be more susceptible to ASD-related risk factors and aggravates a subtype of ASD with GI comorbidities.

Keywords: Autism spectrum disorder; Autism-like behaviors; Enteric nervous system; Gastrointestinal problems; Vitamin A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / chemically induced
  • Autistic Disorder / metabolism
  • Autistic Disorder / physiopathology*
  • Autistic Disorder / prevention & control
  • Behavior, Animal*
  • Disease Models, Animal
  • Enteric Nervous System / physiopathology*
  • Gastrointestinal Motility*
  • Intestines / innervation*
  • Proto-Oncogene Proteins c-ret / genetics
  • Proto-Oncogene Proteins c-ret / metabolism
  • Rats, Sprague-Dawley
  • Retinoic Acid Receptor alpha / metabolism
  • Risk Factors
  • Valproic Acid
  • Vitamin A / therapeutic use
  • Vitamin A Deficiency / complications*
  • Vitamin A Deficiency / drug therapy
  • Vitamin A Deficiency / metabolism
  • Vitamin A Deficiency / physiopathology

Substances

  • Rara protein, rat
  • Retinoic Acid Receptor alpha
  • Vitamin A
  • Valproic Acid
  • Proto-Oncogene Proteins c-ret
  • Ret protein, rat