Increased BDNF expression in fetal brain in the valproic acid model of autism

Mol Cell Neurosci. 2014 Mar;59:57-62. doi: 10.1016/j.mcn.2014.01.007. Epub 2014 Jan 28.

Abstract

Human fetal exposure to valproic acid (VPA), a widely-used anti-epileptic and mood-stabilizing drug, leads to an increased incidence of behavioral and intellectual impairments including autism; VPA administration to pregnant rats and mice at gestational days 12.5 (E12.5) or E13.5 leads to autistic-like symptoms in the offspring and is widely used as an animal model for autism. We report here that this VPA administration protocol transiently increased both BDNF mRNA and BDNF protein levels 5-6-fold in the fetal mouse brain. VPA exposure in utero induced smaller increases in the expression of mRNA encoding the other neurotrophins, NT3 (2.5-fold) and NT4 (2-fold). Expression of the neurotrophin receptors, trkA, trkB and trkC were minimally affected, while levels of the low-affinity neurotrophin receptor, p75(NTR), doubled. Of the nine 5'-untranslated exons of the mouse BDNF gene, only expression of exons I, IV and VI was stimulated by VPA in utero. In light of the well-established role of BDNF in regulating neurogenesis and the laminar fate of postmitotic neurons in the developing cortex, an aberrant increase in BDNF expression in the fetal brain may contribute to VPA-induced cognitive disorders by altering brain development.

Keywords: Autism spectrum disorder; Brain development; Brain-derived neurotrophic factor; Gene promoters; Neurotrophin; VPA.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autistic Disorder / chemically induced*
  • Autistic Disorder / metabolism
  • Brain / drug effects*
  • Brain / embryology
  • Brain / metabolism
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Female
  • Fetus / drug effects*
  • Fetus / metabolism
  • Maternal-Fetal Exchange
  • Mice
  • Mice, Inbred C57BL
  • Pregnancy
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / metabolism
  • Valproic Acid / pharmacology*
  • Valproic Acid / toxicity

Substances

  • Brain-Derived Neurotrophic Factor
  • RNA, Messenger
  • Receptors, Nerve Growth Factor
  • Valproic Acid