title: Valproate-induced neurodevelopmental deficits in Xenopus laevis tadpoles.
abstract: 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.
authors.affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: James
authors.affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and.
authors.forename: Jenny
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and.
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Ramirez-Vizcarrondo
authors.affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and.
authors.forename: Mashfiq
authors.identifier: http://orcid.org/0000-0002-0964-8255
authors.initials: M
authors.lastname: Hasan
authors.affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and.
authors.forename: Torrey L S
authors.initials: TL
authors.lastname: Truszkowski
authors.affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and.
authors.forename: Phouangmaly M
authors.initials: PM
authors.lastname: Oupravanh
authors.affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and Bard College, Biology Program, Annandale-on-Hudson, New York 12504 khakhalin@bard.edu carlos_aizenman@brown.edu.
authors.forename: Arseny S
authors.initials: AS
authors.lastname: Khakhalin
authors.affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island 02912, and khakhalin@bard.edu carlos_aizenman@brown.edu.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Aizenman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000927:Anticonvulsants / Q000009:adverse effects*; D001362:Avoidance Learning / Q000187:drug effects; D003292:Convulsants / Q000633:toxicity; D003712:Dendrites / Q000187:drug effects / Q000473:pathology; D002658:Developmental Disabilities / Q000139:chemically induced* / Q000503:physiopathology; D004195:Disease Models, Animal; D004924:Escape Reaction / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D010433:Pentylenetetrazole / Q000633:toxicity; D013216:Reflex, Startle / Q000187:drug effects; D012165:Retinal Ganglion Cells / Q000473:pathology / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D013477:Superior Colliculi / Q000187:drug effects / Q000473:pathology; D014635:Valproic Acid / Q000009:adverse effects*; D014786:Vision Disorders / Q000209:etiology; D014982:Xenopus laevis
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D014635:Valproic Acid; D010433:Pentylenetetrazole
keywords: Xenopus; autism; developmental; neural circuit; valproic acid