Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally

Background: The amygdala controls socioemotional behavior and has consistently been implicated in the etiology of autism spectrum disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. Prenatal exposure to VPA leads to an ASD phenotype in both humans and rats and has become a commonly used tool to model the complexity of ASD symptoms in the laboratory. Here, we examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD. Methods: Rat dams received oral gavage of VPA (500 mg/kg) or saline daily between E11 and 13. Socioemotional behavior was tracked across development in both sexes. RNA sequencing and proteomics were performed on amygdala samples from male rats across development. Results: Effects of VPA on time spent in social proximity and anxiety-like behavior were sex dependent, with social abnormalities presenting in males and heightened anxiety in females. Across time VPA stunted developmental and immune, but enhanced cellular death and disorder, pathways in the amygdala relative to saline controls. At postnatal day 10, gene pathways involved in nervous system and cellular development displayed predicted activations in prenatally exposed VPA amygdala samples. By juvenile age, however, transcriptomic and proteomic pathways displayed reductions in cellular growth and neural development. Alterations in immune pathways, calcium signaling, Rho GTPases, and protein kinase A signaling were also observed. Conclusions: As behavioral, developmental, and genomic alterations are similar to those reported in ASD, these results lend support to prenatal exposure to VPA as a useful tool for understanding how developmental insults to molecular pathways in the amygdala give rise to ASD-related syndromes. Electronic supplementary material The online version of this article (doi:10.1186/s13229-017-0160-x) contains supplementary material, which is available to authorized users

Additional file 1: Table S1-6. of Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally

Table S1. Canonical RNA sequencing pathways differing from P10 to 21 in (A) both VPA and saline amygdala, (B) exclusively in saline amygdala, or (C) exclusively in VPA amygdala. Table S2. Canonical RNA sequencing pathways differing between saline and VPA amygdala at (A) P10 and (B) P21. Table S3. Canonical Proteomic Pathways differing between saline and VPA amygdala at P21. Table S4. Diseases and Functions RNA Sequencing Categories differing from P10 to 21 in (A) both VPA and saline amygdala, (B) exclusively in saline amygdala, or (C) exclusively in VPA amygdala both VPA and saline amygdala. Table S5. Diseases and functions RNA sequencing categories differing between saline and VPA amygdala at (A) P10 and (B) P21. Table S6. Diseases and functions proteomic categories differing between saline and VPA amygdala at P21. (DOCX 86 kb

Additional file 2: Figure S1. of Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally

RNA sequencing pathways differentially altered across development between VPA and saline amygdala. Pathways with significant time (P10–21) by treatment (VPA/saline) effects are displayed. Treatment effects did not reach statistical significance after FDR multiple comparison correction, thus Ingenuity Pathway Analyses were run on genes with uncorrected p < 0.05 treatment effects at P10 (n = 542) and P21 (n = 406). Canonical pathways and diseases and functions categories with predicted activation or inhibition differences were broadly categorized into the following groups: cellular development and growth; nervous system development and function; immune system, cancer, disease; cell/organismal death; metabolism; and developmental, neurological, or psychological disorder. (PDF 59 kb