title: Prenatal immune activation induces maturation-dependent alterations in the prefrontal GABAergic transcriptome.
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.
authors: *To whom correspondence should be addressed; tel: +41 44 655 7403, fax: +41 44 655 7203, e-mail: urmeyer@ethz.ch.
authors: Juliet
authors: J
authors: Richetto
authors: Francesca
authors: F
authors: Calabrese
authors: Marco A
authors: MA
authors: Riva
authors: Urs
authors: U
authors: Meyer
mesh_terms: D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000276:immunology*; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics* / Q000503:physiopathology; D012559:Schizophrenia / Q000209:etiology / Q000235:genetics / Q000276:immunology; D059467:Transcriptome / Q000235:genetics*; D005680:gamma-Aminobutyric Acid / Q000235:genetics
chemical_list: D005680:gamma-Aminobutyric Acid
keywords: GABA; immune activation; infection; prefrontal cortex; schizophrenia