Related Experiment Video
Updated: May 3, 2026
Dynamic Clamp Methods to Investigate Impaired Neuronal Excitability Associated with Autism
Published on: October 17, 2025
Increased BDNF expression in fetal brain in the valproic acid model of autism
Luis E F Almeida1, Clinton D Roby1, Bruce K Krueger2
1Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Insights
Valproic acid (VPA) exposure in pregnant mice increases brain-derived neurotrophic factor (BDNF) in fetal brains, potentially contributing to autism-like symptoms and cognitive disorders in offspring.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Valproic acid (VPA) is a medication used to treat epilepsy and bipolar disorder.
- In utero exposure to VPA is linked to an increased incidence of autism spectrum disorder (ASD) in humans.
- VPA administration during critical developmental periods in rodents serves as a common animal model for autism.
Purpose of the Study:
- To investigate the effects of in utero VPA exposure on neurotrophin expression in the developing mouse brain.
- To explore the potential role of altered neurotrophin signaling in VPA-induced developmental abnormalities.
Main Methods:
- Pregnant mice were administered VPA at specific gestational days (E12.5 or E13.5).
- Quantitative analysis of mRNA and protein levels for BDNF, NT3, and NT4 in fetal mouse brains.
- Assessment of neurotrophin receptor expression (trkA, trkB, trkC, p75(NTR)).
Main Results:
- VPA exposure significantly increased BDNF mRNA and protein levels (5-6 fold) in fetal brains.
- Modest increases in NT3 (2.5 fold) and NT4 (2 fold) mRNA were observed.
- Levels of p75(NTR) doubled, while trkA, trkB, and trkC receptor expression remained largely unchanged.
- Specific BDNF 5'-untranslated exons (I, IV, VI) showed increased expression.
Conclusions:
- In utero VPA exposure causes a transient but significant upregulation of BDNF in the developing mouse brain.
- Aberrant BDNF signaling, particularly involving specific exons, may disrupt normal brain development.
- Altered neurotrophin expression is a potential mechanism underlying VPA-induced cognitive and behavioral deficits, including autism-like symptoms.
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.
