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Cited by 80Autism Spectrum Disorder ResearchPharmacological Effects and Toxicity StudiesGenetics and Neurodevelopmental Disorders

Repeated prenatal exposure to valproic acid results in cerebellar hypoplasia and ataxia

Main, Stacey L., Kulesza, Randy J.·2017·Neuroscience
DOI 10.1016/j.neuroscience.2016.10.052
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Abstract

Autism spectrum disorder (ASD) is a developmental brain disorder characterized by restricted and repetitive patterns of behavior, social and communication defects, and is commonly associated with difficulties with motor coordination. The etiology of ASD, while mostly idiopathic, has been linked to hereditary factors and teratogens, such as valproic acid (VPA). VPA is used clinically to treat epilepsy, mood disorders, and in the prevention of migraines. The use of VPA during pregnancy significantly increases the risk of ASD in the offspring. Neuropathological studies show decreased cerebellar function in patients with ASD, resulting in gait, balance and coordination impairments. Herein, we have exposed pregnant rats to a repeated oral dose of VPA on embryonic days 10 and 12 and performed a detailed investigation of the structure and function of the cerebellar vermis. We found that throughout all ten lobules of the cerebellar vermis, Purkinje cells were significantly smaller and expression of the calcium binding protein calbindin (CB) was significantly reduced. We also found that dendritic arbors of Purkinje cells were shorter and less complex. Additionally, animals exposed to a repeated dose of VPA performed significantly worse in a number of motor tasks, including beam walking and the rotarod. These results suggest that repeated embryonic exposure to VPA induces significant cerebellar dysfunction and is an effective animal model to study the cerebellar alterations in ASD.

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  • Ectopic cells and reduced size and complexity of dendritic branching of Purkinje cells are seen in VPA-exposed rodents.

    “Ectopic cells and reduced size and complexity of dendritic branching of Purkinje cells are seen in VPA-exposed rodents [228].”

    From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [228]

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Authors
Main, S. L., & Kulesza, R. J.
Affiliations
Lake Erie College of Osteopathic Medicine (US)
Corresponding author
Kulesza, Randy J.
ORCID
Kulesza, Randy J.
Venue
Neuroscience
Publisher
Elsevier BV
Published
2017-01
Volume
340
Pages
34-47
ISSN
0306-4522 (ISSN-L)
DOI
10.1016/j.neuroscience.2016.10.052
OpenAlex
W2540237814
Cited by
80
References
107
Citations by year
2026: 7 · 2025: 8 · 2024: 16 · 2023: 6 · 2022: 9 · 2021: 8 · 2020: 10 · 2019: 5 · 2018: 7 · 2017: 4
FWCI
3.40
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Lake Erie College of Osteopathic Medicine
  • Lake Erie Consortium for Medical Training
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
valproic acid, prenatal drug exposure, autism spectrum disorder, cerebellar hypoplasia, cerebellar vermis, Purkinje cells, calbindin, motor coordination, ataxia, animal models of autism, teratogens, beam walking, rotarod test
MeSH terms
Administration, Oral, Animals, Ataxia, Cerebellum, Developmental Disabilities, Disease Models, Animal, Female, Male, Nervous System Malformations, Pregnancy, Prenatal Exposure Delayed Effects, Purkinje Cells, Reflex, Valproic Acid, Walking, Rats, Sprague-Dawley, Rotarod Performance Test, Cell Size, Calbindins

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