The critical period of valproate exposure to induce autistic symptoms in Sprague-Dawley rats

Toxicol Lett. 2011 Mar 5;201(2):137-42. doi: 10.1016/j.toxlet.2010.12.018. Epub 2010 Dec 30.


Prenatal exposure to valproic acid (VPA) induces neural tube defects and impairment in social behaviors related to autistic spectrum disorder in newborns, which make it a useful animal model of autism. In this study, we compared the effects of different time window of prenatal valproic acid exposure for inducing the altered social behaviors relevant to autism from embryonic day 7 to embryonic day 15 in Sprague-Dawley rats to determine the critical periods for the impairment. Compared to E7, E9.5 and E15 exposure, VPA exposure at E12 showed most significant changes in behaviors over control animals with reduced sociability and social preference. E9.5 exposure to valproic acid showed strong reproductive toxicity including decrease in the number of live birth. In general, exposure at E15 showed only marginal effects on reproduction and social behaviors. Finally, VPA-exposed rats at E12 were more sensitive to electric shock than VPA-exposed rats at any other periods. These results suggested that E12 is the critical period in rats when valproate exposure has prominent effects for inducing the altered social behavior similar to human autistic behavior.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / toxicity*
  • Autistic Disorder / chemically induced*
  • Disease Models, Animal
  • Electroshock
  • Female
  • Fetus / drug effects*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta
  • Neural Tube Defects / chemically induced
  • Pregnancy
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA / physiology
  • Social Behavior
  • Valproic Acid / toxicity*


  • Anticonvulsants
  • Receptors, GABA
  • Valproic Acid
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3