Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice

Moldrich, Randal X., Leanage, Gayeshika, She, David, Dolan-Evans, Elliot, Nelson, Michael, Reza, Nargis and Reutens, David C. (2013) Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice. Behavioural Brain Research, 257 253-264. doi:10.1016/j.bbr.2013.09.049

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Author Moldrich, Randal X.
Leanage, Gayeshika
She, David
Dolan-Evans, Elliot
Nelson, Michael
Reza, Nargis
Reutens, David C.
Title Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice
Formatted title
Inhibition of histone deacetylase in utero causes sociability deficits in postnatal mice
Journal name Behavioural Brain Research   Check publisher's open access policy
ISSN 0166-4328
1872-7549
Publication date 2013-11-15
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.bbr.2013.09.049
Open Access Status Not Open Access
Volume 257
Start page 253
End page 264
Total pages 12
Place of publication Amsterdam, Netherlands
Publisher Elsevier
Language eng
Formatted abstract
Highlights
• Valproate (VPA) exposure in utero causes language delay and autism.
• VPA was compared to a specific histone deacetylase inhibitor trichostatin A (TSA).
• VPA and TSA caused histone deacetylation and methylation in mice in utero.
In utero VPA and TSA inhibited postnatal communication and sociability.
• VPA can cause developmental delay by histone deacetylase inhibition.

Exposure to sodium valproate (VPA) in utero increases the risk of language impairment and a diagnosis of autism spectrum disorder (ASD). Mice exposed to VPA while in utero have also shown postnatal social deficits. Inhibition of histone deacetylase (HDAC) is one of VPA's many biological effects. The main objective of this study was to test the hypothesis that HDAC inhibition causes these behavioral outcomes following prenatal VPA exposure in mice. We exposed embryonic mice to VPA, the HDAC inhibitor trichostatin A (TSA), or vehicle controls. TSA (1 mg/kg) inhibited HDAC in embryonic tissue at a level comparable to 600 mg/kg VPA, resulting in significant increases in histone H3 and H4 acetylation, and histone H3 lysine 4 tri-methylation. Postnatally, decreases in ultrasonic vocalization, olfactory motivation and sociability were observed in TSA and VPA-exposed pups. Treated mice exhibited elevated digging and grooming suggestive of mild restrictive and repetitive behaviors. Olfactory social preference, social novelty and habituation were normal. Together, these data indicate that embryonic HDAC inhibition alone can cause abnormal social behaviors in mice. This result serves as a molecular understanding of infant outcomes following mild VPA exposure in utero.
Keyword Sodium valproate
Autism
Trichostatin A
Histone deacetylase
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
Centre for Advanced Imaging Publications
UQ Diamantina Institute Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 17 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 19 times in Scopus Article | Citations
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Created: Thu, 17 Oct 2013, 03:04:49 EST by Sandrine Ducrot on behalf of Centre for Advanced Imaging