title: Maternal immune activation induces GAD1 and GAD2 promoter 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.
authors.affiliation: a Physiology and Behavior Laboratory; ETH Zurich ; Schwerzenbach , Switzerland.
authors.forename: Marie Anaïs
authors.initials: MA
authors.lastname: Labouesse
authors.affiliation: b Psychiatric Institute, Department of Psychiatry; College of Medicine; University of Illinois at Chicago ; Chicago , Illinois , USA.
authors.forename: Erbo
authors.initials: E
authors.lastname: Dong
authors.affiliation: b Psychiatric Institute, Department of Psychiatry; College of Medicine; University of Illinois at Chicago ; Chicago , Illinois , USA.
authors.forename: Dennis Robert
authors.initials: DR
authors.lastname: Grayson
authors.affiliation: b Psychiatric Institute, Department of Psychiatry; College of Medicine; University of Illinois at Chicago ; Chicago , Illinois , USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Guidotti
authors.affiliation: a Physiology and Behavior Laboratory; ETH Zurich ; Schwerzenbach , Switzerland.|c Institute of Pharmacology and Toxicology; University of Zurich-Vetsuisse ; Zurich , Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Meyer
mesh_terms: D000818:Animals; D001665:Binding Sites; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics*; D007113:Immunity, Innate; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism; D051379:Mice; D017397:Prefrontal Cortex; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D012333:RNA, Messenger; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2
keywords: Autism; DNA methylation; GABA, maternal infection; chromatin; epigenetics; poly(I:C); prefrontal cortex; prenatal immune activation; schizophrenia