Acute prenatal exposure to a moderate dose of valproic acid increases social behavior and alters gene expression in rats - PubMed (original) (raw)

Acute prenatal exposure to a moderate dose of valproic acid increases social behavior and alters gene expression in rats

Ori S Cohen et al. Int J Dev Neurosci. 2013 Dec.

Abstract

Prenatal exposure to moderate doses of valproic acid (VPA) produces brainstem abnormalities, while higher doses of this teratogen elicit social deficits in the rat. In this pilot study, we examined effects of prenatal exposure to a moderate dose of VPA on behavior and on transcriptomic expression in three brain regions that mediate social behavior. Pregnant Long Evans rats were injected with 350 mg/kg VPA or saline on gestational day 13. A modified social interaction test was used to assess social behavior and social preference/avoidance during early and late adolescence and in adulthood. VPA-exposed animals demonstrated more social investigation and play fighting than control animals. Social investigation, play fighting, and contact behavior also differed as a function of age; the frequency of these behaviors increased in late adolescence. Social preference and locomotor activity under social circumstances were unaffected by treatment or age. Thus, a moderate prenatal dose of VPA produces behavioral alterations that are substantially different from the outcomes that occur following exposure to a higher dose. At adulthood, VPA-exposed subjects exhibited transcriptomic abnormalities in three brain regions: anterior amygdala, cerebellar vermis, and orbitofrontal cortex. A common feature among the proteins encoded by the dysregulated genes was their ability to be modulated by acetylation. Analysis of the expression of individual exons also revealed that genes involved in post-translational modification and epigenetic regulation had particular isoforms that were ubiquitously dysregulated across brain regions. The vulnerability of these genes to the epigenetic effects of VPA may highlight potential mechanisms by which prenatal VPA exposure alters the development of social behavior.

Keywords: AA; ANCOVA; ANOVA; Adolescence; Autism; CREB; CREB binding protein; CREBBP; CV; DNA; G; GABA; Gene expression; HDAC; HDACi; ID; IUTs; OFC; P; P. C.; RNA; RTS; Rubinstein–Taybi syndrome; Sex differences; Social interaction; Teratogen; VPA; aa; amino acid; analysis of covariance; analysis of variance; anterior amygdala; cAMP response element binding protein; cerebellar vermis; deoxyribose nucleic acid; gamma-aminobutyric acid; gestational day; histone deacetylase; histone deacetylase inhibitor; i.p.; identity; intersection/union tests; intraperitoneal; mRNA; messenger RNA; mg/kg; milligrams per kilogram body weight; orbitofrontal cortex; postnatal day; principal component; ribonucleic acid; valproic acid.

Copyright © 2013 ISDN. Published by Elsevier Ltd. All rights reserved.

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Figures

Figure 1

Figure 1

Effects of Exposure to Valproic Acid on Social Behavior. Four features of social behavior as well as locomotor activity were analyzed from a modified social interaction test. Both social investigation and play fighting, were significantly increased in animals exposed to valproic acid when the data were collapsed across age. Three features, social investigation, play fighting, and contact behavior, were significantly increased in 42-day-old animals compared with those tested on P28 or P75 (data collapsed across treatment). Neither social motivation nor locomotor activity showed a significant effect of age or prenatal treatment. Significant differences between saline- and valproic acid-exposed animals: * p < 0.05, ** p<0.01. Significant differences between age groups: # p < 0.01, ## p<0.001. Bars show the mean for each group, t-bars depict the standard error of the mean. No differences between the sexes were identified for any of the measures, thus data were collapsed across sex.

Figure 2

Figure 2

a. Principal Components Analysis of Rat Brain Transcriptome. Individual data points (three per subject, one per brain region) were mapped to the first three principal components (P. C.) of gene expression variance derived from the entire rat transcriptome. Data points from each brain region showed very strong correspondence with each other but no relation to prenatal treatment, while data from each individual subject was clearly distributed across the three clusters defined by brain region, with the exception of a single subject that was removed from all subsequent analyses. This demonstrates the brain-regional specificity of the co-expression of genes in the rat transcriptome and the relative integrity of its global characteristics and gene-wise correlations despite prenatal VPA exposure. b. Venn Diagram of Whole-Gene Clusters Significantly Dysregulated by VPA Treatment in Each Brain Region Most genes dysregulated by prenatal VPA treatment were only affected in one of the three evaluated brain regions. In contrast to these regionally specific effects of prenatal VPA exposure on gene expression, there were also 139 instances where prenatal VPA exposure had long-lasting effects on gene expression in two of the three regions, with the anterior amygdala and orbitofrontal cortex highest in similarity. There were also 5 instances where the effects of VPA were persistent and ubiquitous across all three brain regions

Figure 3

Figure 3

a. Venn Diagram of Genes with Significantly Dysregulated Alternative Splicing by VPA Treatment in Each Brain Region Most genes with dysregulated alternative splicing by prenatal VPA treatment were only affected in one of the three evaluated brain regions. In contrast to these regionally specific effects of prenatal VPA exposure on gene expression, there were also 321 instances where prenatal VPA exposure had long-lasting effects on gene expression in two of the three regions, with the cerebellar vermis and orbitofrontal cortex having highest in similarity. There were also 51 instances where the effects of VPA were persistent and ubiquitous across all three brain regions. b. Exonic expression of Serine/threonine-protein kinase N1 (Pkn1). Exonic expression of Pkn1 across all three brain regions: anterior amygdala (AA), cerebellar vermis (CV), and oribitofrontal cortex (OFC) from 5 prenatally valproic acid (VPA) exposed rats and 6 saline control (CNT) rats. Differential expression of exon 19 is seen between exposure groups. c. Exonic expression of Prolyl endopeptidase (Prep) Exonic expression of Prep across all three brain regions: anterior amygdala (AA), cerebellar vermis (CV), and oribitofrontal cortex (OFC) from 5 prenatally valproic acid (VPA) exposed rats and 6 saline control (CNT) rats. Differential expressions of exons 1 and 8 are seen between exposure groups for all three brain regions.

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