Autism-like behaviours with transient histone hyperacetylation in mice treated prenatally with valproic acid
Open accessAbstract
Maternal use of valproic acid (VPA) during pregnancy has been implicated in the aetiology of autism spectrum disorders in children, and rodents prenatally exposed to VPA showed behavioural alterations similar to those observed in humans with autism. However, the exact mechanism for VPA-induced behavioural alterations is not known. To study this point, we examined the effects of prenatal exposure to VPA and valpromide, a VPA analog lacking histone deacetylase inhibition activity, on behaviours, cortical pathology and histone acetylation levels in mice. Mice exposed to VPA at embryonic day 12.5 (E12.5), but not at E9 and E14.5, displayed social interaction deficits, anxiety-like behaviour and memory deficits at age 4–8 wk. In contrast to male mice, the social interaction deficits (a decrease in sniffing behaviour) were not observed in female mice at age 8 wk. The exposure to VPA at E12.5 decreased the number of Nissl-positive cells in the middle and lower layers of the prefrontal cortex and in the lower layers of the somatosensory cortex at age 8 wk. Furthermore, VPA exposure caused a transient increase in acetylated histone levels in the embryonic brain, followed by an increase in apoptotic cell death in the neocortex and a decrease in cell proliferation in the ganglionic eminence. In contrast, prenatal exposure to valpromide at E12.5 did not affect the behavioural, biochemical and histological parameters. Furthermore, these findings suggest that VPA-induced histone hyperacetylation plays a key role in cortical pathology and abnormal autism-like behaviours in mice.
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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 [186]
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- Authors
- Kataoka, S., Takuma, K., Hara, Y., Maeda, Y., Ago, Y., & Matsuda, T.
- Affiliations
- The University of Osaka (JP)
- Kanazawa University (JP)
- Corresponding author
- Matsuda, Toshio
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-02-01
- Volume
- 16
- Issue
- 1
- Pages
- 91-103
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- OpenAlex
- W2163492066
- Cited by
- 341
- References
- 56
- Citations by year
- 2026: 15 · 2025: 33 · 2024: 30 · 2023: 30 · 2022: 40 · 2021: 26 · 2020: 24 · 2019: 26 · 2018: 15 · 2017: 24 · 2016: 27 · 2015: 16 · 2014: 11 · 2013: 18 · 2012: 6
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- valproic acid, prenatal drug exposure, autism spectrum disorder, histone hyperacetylation, histone deacetylase inhibition, valpromide, social interaction deficits, anxiety-like behavior, memory impairment, cortical pathology, prefrontal cortex, somatosensory cortex, neuronal apoptosis, ganglionic eminence, sex differences
- MeSH terms
- Acetylation, Animals, Autistic Disorder, Cell Movement, Cerebral Cortex, Female, Histones, Interpersonal Relations, Male, Mice, Inbred ICR, Pregnancy, Prenatal Exposure Delayed Effects, Valproic Acid, Maze Learning, Mice
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