Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring

Science. 2014 Feb 7;343(6171):675-9. doi: 10.1126/science.1247190.

Abstract

We report that the oxytocin-mediated neuroprotective γ-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naïve mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autistic Disorder / chemically induced*
  • Autistic Disorder / genetics*
  • Autistic Disorder / metabolism
  • Behavior, Animal
  • Bumetanide / administration & dosage
  • Chlorides / metabolism
  • Cytoprotection*
  • Disease Models, Animal
  • Female
  • Fragile X Mental Retardation Protein / genetics
  • Maternal-Fetal Exchange
  • Mice
  • Oxytocin / metabolism*
  • Parturition
  • Pregnancy
  • Rats
  • Valproic Acid / pharmacology
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Chlorides
  • Bumetanide
  • Fragile X Mental Retardation Protein
  • Oxytocin
  • gamma-Aminobutyric Acid
  • Valproic Acid