Acute prenatal exposure to a moderate dose of valproic acid increases social behavior and alters gene expression in rats.
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.
Psychiatric Genetic Epidemiology & Neurobiology Laboratory (PsychGENe Lab), Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY 13210, United States.
Ori S
OS
Cohen
Elena I
EI
Varlinskaya
Carey A
CA
Wilson
Stephen J
SJ
Glatt
Sandra M
SM
Mooney
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000009:adverse effects*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D008297:Male; D046228:Microarray Analysis; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D012919:Social Behavior; D014635:Valproic Acid / Q000009:adverse effects*
D000927:Anticonvulsants; D012333:RNA, Messenger; D014635:Valproic Acid
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