Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain. A possible new animal model of autism
Abstract
The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20mg/kg or 100mg/kg) continuously during the last 9-12 days of pregnancy and during the lactation period until sacrifice on the 23rd postnatal day. Total number of neocortical neurons was estimated using the optical fractionator and frontal cortical thicknesses were sampled in VPA exposed pups compared with an unexposed control group. We found that pups exposed to 20mg/kg and 100mg/kg doses of VPA had statistically significant higher total number of neurons in neocortex by 15.8% and 12.3%, respectively (p<0.05) compared to controls amounting to 15.5×10(6) neocortical neurons (p<0.01). There was no statistical difference between the two VPA groups. Pups exposed to100mg/kg, but not to 20mg/kg VPA displayed a significant (p<0.05) broader (7.5%) of frontal cortical thickness compared to controls. Our results support the hypothesis that fetal exposure of VPA may interfere with normal brain development by disturbing neocortical organization, resulting in overgrowth of frontal lobes and increased neuronal cell numbers. The results indirectly suggest that prenatal VPA may contribute as a causative factor in the brain developmental disturbances equivalent to those seen in human autism spectrum disorders. We therefore suggest that this version of the VPA model may provide a translational model of autism.
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Cell density is increased in the neocortex with low-dose VPA and decreased in the prefrontal and somatosensory cortex with high-dose VPA.
“Cell density is increased in the neocortex with a low dose [307] and decreased in the prefrontal and somatosensory cortex with a high dose of VPA [186].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [307]
Acute high-dose VPA exposure reduces cortical thickness, whereas chronic low-dose exposure increases cortical thickness.
“Acute exposure at a high dose reduces cortical thickness [250], whereas chronic exposure to a low dose increases cortical thickness [307].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [307]
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Autism spectrum disorder: neuropathology and animal models
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- Authors
- Sabers, A., Bertelsen, F. C. B., Scheel-Krüger, J., Nyengaard, J. R., & Møller, A.
- Affiliations
- Rigshospitalet (DK)
- Aarhus University (DK)
- Corresponding author
- Sabers, Anne
- Venue
- Neuroscience Letters
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 580
- Pages
- 12-16
- ISSN
- 0304-3940 (ISSN-L)
- OpenAlex
- W2113630587
- Cited by
- 43
- References
- 51
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 5 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 6 · 2017: 8 · 2016: 4 · 2015: 4
- FWCI
- 5.02
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-02-19)
- Open access
- closed
- Locations
- Neuroscience Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Villum Fonden (00008721)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- valproic acid, prenatal drug exposure, autism spectrum disorder, animal models of autism, neocortical neurons, cortical thickness, brain development, lactation, developmental neurotoxicity
- MeSH terms
- Animals, Anticonvulsants, Autistic Disorder, Cell Count, Disease Models, Animal, Female, Lactation, Neurons, Pregnancy, Prenatal Exposure Delayed Effects, Psychotropic Drugs, Valproic Acid, Rats, Wistar, Maternal Exposure, Neocortex
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