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Schizophr Bull. 2014 Mar;40(2):351-61. doi: 10.1093/schbul/sbs195. Epub 2013 Jan 17.

Prenatal immune activation induces maturation-dependent alterations in the prefrontal GABAergic transcriptome.

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*To whom correspondence should be addressed; tel: +41 44 655 7403, fax: +41 44 655 7203, e-mail: urmeyer@ethz.ch.

Abstract

Neuronal dysfunctions in the cortical GABAergic system have been widely documented in neuropsychiatric disorders with prenatal infectious etiologies, including schizophrenia. At least some of these abnormalities may stem from transcriptional impairments in the GABAergic transcriptome. However, the extent to which prenatal exposure to immune challenge can induce long-term alterations in GABAergic gene transcription remains largely elusive. Here, we use an established mouse model of prenatal immune activation induced by maternal gestational administration of the viral mimetic poly(I:C) (= polyriboinosinic-polyribocytidilic acid) to demonstrate that prenatal immune activation causes maturation-dependent alterations in prefrontal GABAergic gene expression. The spectrum of abnormalities included altered mRNA expression levels of enzymes regulating γ-aminobutyric acid (GABA) biosynthesis (glutamic acid decarboxylase 65-kDa [GAD65] and GAD67), vesicular GABA transporter (VGAT), alpha-subunits of the GABA(A) receptor (α2, α3, α4, and α5), and the chloride transporters sodium-potassium-chloride cotransporter 1 and potassium-chloride cotransporter 2. Additional western blot analyses confirmed the deficits in prefrontal GAD65/GAD67 and VGAT expression at the protein level. Intriguingly, the prefrontal GABAergic transcriptome was found to be more strongly affected in adult compared with peripubertal offspring born to immune-challenged mothers, and these age-dependent changes in GABAergic gene expression were paralleled by an adult onset of working memory deficiency. Collectively, our data emphasize a critical impact of prenatal immune-related insults on long-term GABAergic changes relevant to neuropsychiatric disorders with prenatal infectious etiologies, especially for those with delayed onset in early adulthood.

KEYWORDS:

GABA; immune activation; infection; prefrontal cortex; schizophrenia

PMID:
23328159
PMCID:
PMC3932076
DOI:
10.1093/schbul/sbs195
[Indexed for MEDLINE]
Free PMC Article

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