Deficits in temporal processing in mice prenatally exposed to Valproic Acid

Eur J Neurosci. 2018 Mar;47(6):619-630. doi: 10.1111/ejn.13621. Epub 2017 Jul 3.


Temporal processing in the seconds-to-minutes range, known as interval timing, is a crucial cognitive function that requires activation of cortico-striatal circuits via dopaminergic-glutamatergic pathways. In humans, both children and adults with autism spectrum disorders (ASD) present alterations in their estimation of time intervals. At present, there are no records of interval timing studies in animal models of ASD. Hence, the objective of the present work was to evaluate interval timing in a mouse model of prenatal exposure to valproic acid (VPA) - a treatment used to induce human-like autistic features in rodent models. Animals were assessed for their ability to acquire timing responses in 15-s and 45-s peak-interval (PI) procedures. Our results indicate that both female and male mice prenatally exposed to VPA present decreased timing accuracy and precision compared to control groups, as well as deviations from the scalar property. Moreover, the observed timing deficits in male VPA mice were reversed after early social enrichment. Furthermore, catecholamine determination by HPLC-ED indicated significant differences in striatal dopaminergic, but not serotonergic, content in female and male VPA mice, consistent with previously identified alterations in dopamine metabolism in ASD. These deficits in temporal processing in a mouse model of autism complement previous results in humans, and provide a useful tool for further behavioral and pharmacological studies.

Keywords: autism spectrum disorder; cortico-striatal circuits; dopamine; interval timing; valproic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autism Spectrum Disorder / metabolism
  • Autism Spectrum Disorder / physiopathology*
  • Behavior, Animal / physiology
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Female
  • GABA Agents / pharmacology*
  • Male
  • Mice
  • Neostriatum / metabolism*
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Prenatal Exposure Delayed Effects / metabolism
  • Prenatal Exposure Delayed Effects / physiopathology*
  • Psychomotor Performance / physiology*
  • Serotonin / metabolism
  • Social Behavior
  • Time Perception / physiology*
  • Valproic Acid / pharmacology*


  • GABA Agents
  • Serotonin
  • Valproic Acid
  • Dopamine