Maternal immune activation inducesGAD1andGAD2promoter remodeling in the offspring prefrontal cortex

Abstract

Maternal infection during pregnancy increases the risk of neurodevelopmental disorders in the offspring. In addition to its influence on other neuronal systems, this early-life environmental adversity has been shown to negatively affect cortical γ-aminobutyric acid (GABA) functions in adult life, including impaired prefrontal expression of enzymes required for GABA synthesis. The underlying molecular processes, however, remain largely unknown. In the present study, we explored whether epigenetic modifications represent a mechanism whereby maternal infection during pregnancy can induce such GABAergic impairments in the offspring. We used an established mouse model of prenatal immune challenge that is based on maternal treatment with the viral mimetic poly(I:C). We found that prenatal immune activation increased prefrontal levels of 5-methylated cytosines (5mC) and 5-hydroxymethylated cytosines (5hmC) in the promoter region of GAD1, which encodes the 67-kDa isoform of the GABA-synthesising enzyme glutamic acid decarboxylase (GAD67). The early-life challenge also increased 5mC levels at the promoter region of GAD2, which encodes the 65-kDa GAD isoform (GAD65). These effects were accompanied by elevated GAD1 and GAD2 promoter binding of methyl CpG-binding protein 2 (MeCP2) and by reduced GAD67 and GAD65 mRNA expression. Moreover, the epigenetic modifications at the GAD1 promoter correlated with prenatal infection-induced impairments in working memory and social interaction. Our study thus highlights that hypermethylation of GAD1 and GAD2 promoters may be an important molecular mechanism linking prenatal infection to presynaptic GABAergic impairments and associated behavioral and cognitive abnormalities in the offspring.

Genome-Wide Transcriptional Profiling and Structural Magnetic Resonance Imaging in the Maternal Immune Activation Model of Neurodevelopmental Disorders

“…It should be pointed out, however, that the correlative analyses between DNA methylation and gene expression levels were based on small sample sizes (N = 5-6 animals per group), and therefore, they might have been underpowered. Nevertheless, our findings are in agreement with previous studies showing prenatal immune activation in rats or mice can induce that various epigenetic changes such as DNA hyper-or hypomethylation, histone modifications, and altered micro-RNA expression, some of which likely affect the expression of corresponding genes (Connor et al 2012;Tang et al 2013;Basil et al 2014;Labouesse et al 2015;Richetto et al, 2016).…”

Maternal immune activation alters glutamic acid decarboxylase-67 expression in the brains of adult rat offspring

“…Our findings of decreased levels of GAD 67 mRNA in the prelimbic cortex of the offspring at P60 are in agreement with previous studies of the PFC in the MIA mouse model (Richetto et al, 2013, 2014; Labouesse et al, 2015). However, here we add regional specificity by localizing the decrease to the prelimbic subdivision of the PFC, as opposed to other PFC subregions.…”

The Role of the Immune System in Autism Spectrum Disorder

“…Significantly, they showed that several autism-relevant traits only persisted through the paternal line, without any further intervention, through the F2 and even the F3 generations, resulting in significant differences in gene expression. A 2015 epigenetic study also using a single poly (I:C) injection found significantly increased rates of 5-methylcytosine and 5-hydroxymethylcytosine on the glutamic acid decarboxylase (GAD1) promoter, which synthesizes the neurotransmitter GABA (Labouesse et al, 2015). These changes correlated with social interaction and working memory impairments and are similar to GABA and GAD1 changes observed in related disorders such as schizophrenia.…”