Sera from children with autism induce autistic features which can be rescued with a CNTF small peptide mimetic in rats

PLoS One. 2015 Mar 13;10(3):e0118627. doi: 10.1371/journal.pone.0118627. eCollection 2015.

Abstract

Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / blood*
  • Autistic Disorder / drug therapy*
  • Autistic Disorder / pathology
  • Autistic Disorder / physiopathology
  • Behavior, Animal / drug effects
  • Brain-Derived Neurotrophic Factor / genetics
  • Cell Death / drug effects
  • Child, Preschool
  • Ciliary Neurotrophic Factor / chemistry*
  • Developmental Disabilities / drug therapy
  • Developmental Disabilities / etiology
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Male
  • Mice
  • Neurons / drug effects
  • Neurons / pathology
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Oxidative Stress / drug effects
  • Peptidomimetics / pharmacology*
  • Peptidomimetics / therapeutic use
  • Phenotype
  • Rats
  • Social Behavior
  • Vocalization, Animal / drug effects

Substances

  • Brain-Derived Neurotrophic Factor
  • Ciliary Neurotrophic Factor
  • Neuroprotective Agents
  • Peptidomimetics

Grant support

This work was supported in part by the New York State Office of People with Developmental Disabilities and EVER NeuroPharma GmbH, Unterach, Austria. S.F. Kazim is supported by SUNY Downstate/NYSIBR Center for Developmental Neuroscience (CDN) Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.