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

Abstract

BackgroundThe 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.MethodsRat 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.ResultsEffects 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.ConclusionsAs 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 materialThe online version of this article (doi:10.1186/s13229-017-0160-x) contains supplementary material, which is available to authorized users.

Social behavior, neuroimmune markers and glutamic acid decarboxylase levels in a rat model of valproic acid-induced autism

“…These results suggest that the VPA-exposed rats had no interest in communicating and showed an inappropriate social interest in a stranger rat. Our results are consistent with those reported from other studies which showed impaired social behavior in VPA-exposed animals (Liu et al, 2016;Mony et al, 2016;Barrett et al, 2017).…”

A Systematic Review of the Valproic-Acid-Induced Rodent Model of Autism

“…daily between GD 11 and 13, and also found shorter calls which were more apparent in VPA females. However, these offspring demonstrated an increase in call frequency from both VPA sexes [31], in contrast to the other studies which showed decreased call frequency (Table 1). Other impairments include a deviation from the normal sound characteristics of each call type, in that calls had a lower amplitude, there were more flat calls, altered number of complex and downward calls, less variety of call types, and fewer 2-syllable calls [32][33][34][35].…”

“…The oral route was also effective at a higher dose (500-800 mg/kg) to reduce preference between object and conspecific in terms of exploratory behaviours such as nose pokes, and reduce entries towards, or time with, the conspecific (500-800 mg/kg) [31,42,43].…”

“…This occurs by any combination of decreased time in or entries into the unfamiliar chamber, or increased time in or entries into the familiar chamber, or both. The oral route is also effective to reduce social exploration with an increased VPA dose (500-800 mg/kg) [31,42]. One study, Melancia et al [39], used a slightly different protocol whereby the social novelty preference test was conducted in an open field set-up (i.e., no separate chambers), and found a similar effect to the more conventional protocol (Table 1).…”

Prenatal psychosocial stress-induced behavioral and neuroendocrine abnormalities are associated with sex-specific alterations in synaptic transmission and differentially modulated by maternal environment

“…In addition, we detected alterations in transcripts encoding synaptic proteins involved in glutamatergic and GABAergic neurotransmitter systems. Our findings are consistent with other studies examining effects of prenatal insults on amygdalar gene expression which have observed changes in ion transporter complexes, GABAA receptor subunits, as well as ionotropic and metabotropic glutamate receptors (Barrett et al, 2017;Ehrlich et al, 2015;Laloux et al, 2012). Our data, however, identify a number of novel PS responsive transcripts, including genes encoding regulatory proteins known to modulate AMPA receptor trafficking and channel kinetics, such as GSG1L, CACNG5, and CNIH3 (Bissen et al, 2019;Gu et al, 2016), genes encoding proteins involved in postsynaptic stabilization of metabotropic glutamate receptors, such as HOMER3, and GABAA receptor trafficking partner HAP1 (Figure 9) (Mandal et al, 2011;Twelvetrees et al, 2019).…”