Valproate-induced neurodevelopmental deficits in Xenopus laevis tadpoles

J Neurosci. 2015 Feb 18;35(7):3218-29. doi: 10.1523/JNEUROSCI.4050-14.2015.


Autism spectrum disorder (ASD) is increasingly thought to result from low-level deficits in synaptic development and neural circuit formation that cascade into more complex cognitive symptoms. However, the link between synaptic dysfunction and behavior is not well understood. By comparing the effects of abnormal circuit formation and behavioral outcomes across different species, it should be possible to pinpoint the conserved fundamental processes that result in disease. Here we use a novel model for neurodevelopmental disorders in which we expose Xenopus laevis tadpoles to valproic acid (VPA) during a critical time point in brain development at which neurogenesis and neural circuit formation required for sensory processing are occurring. VPA is a commonly prescribed antiepileptic drug with known teratogenic effects. In utero exposure to VPA in humans or rodents results in a higher incidence of ASD or ASD-like behavior later in life. We find that tadpoles exposed to VPA have abnormal sensorimotor and schooling behavior that is accompanied by hyperconnected neural networks in the optic tectum, increased excitatory and inhibitory synaptic drive, elevated levels of spontaneous synaptic activity, and decreased neuronal intrinsic excitability. Consistent with these findings, VPA-treated tadpoles also have increased seizure susceptibility and decreased acoustic startle habituation. These findings indicate that the effects of VPA are remarkably conserved across vertebrate species and that changes in neural circuitry resulting from abnormal developmental pruning can cascade into higher-level behavioral deficits.

Keywords: Xenopus; autism; developmental; neural circuit; valproic acid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Anticonvulsants / adverse effects*
  • Avoidance Learning / drug effects
  • Convulsants / toxicity
  • Dendrites / drug effects
  • Dendrites / pathology
  • Developmental Disabilities / chemically induced*
  • Developmental Disabilities / physiopathology
  • Disease Models, Animal
  • Escape Reaction / drug effects
  • Excitatory Amino Acid Agonists / pharmacology
  • Habituation, Psychophysiologic / drug effects
  • Inhibitory Postsynaptic Potentials / drug effects
  • Inhibitory Postsynaptic Potentials / physiology
  • Pentylenetetrazole / toxicity
  • Reflex, Startle / drug effects
  • Retinal Ganglion Cells / pathology
  • Retinal Ganglion Cells / physiology
  • Seizures / chemically induced
  • Seizures / drug therapy
  • Seizures / pathology
  • Superior Colliculi / drug effects
  • Superior Colliculi / pathology
  • Valproic Acid / adverse effects*
  • Vision Disorders / etiology
  • Xenopus laevis


  • Anticonvulsants
  • Convulsants
  • Excitatory Amino Acid Agonists
  • Valproic Acid
  • Pentylenetetrazole