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.

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

“…It was selected based on previous studies showing that prenatal poly(I:C) exposure during this gestational period causes adult behavioral, cognitive, and neuroanatomical abnormalities relevant to neurodevelopmental brain disorders, including schizophrenia and autism (Meyer et al 2006(Meyer et al , 2008Bitanihirwe et al 2010aBitanihirwe et al , 2010bRichetto et al 2013Richetto et al , 2014Richetto et al , 2015. We previously verified that poly(I:C) administration on GD 17 is effective in terms of eliciting cytokine-associated inflammatory response in maternal and fetal tissues (Meyer et al 2006).…”

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…MIA in rats and mice causes dysfunction of GABAergic circuitry in the hippocampus, amygdala, and cortex (Canetta and Brown, 2012;Meyer, 2014). GABA content decreases (Bitanihirwe et al, 2010), GAD1 gene expression decreases (Deslauriers et al, 2013;Richetto et al, 2013), and GABA receptor subunit expression increases (Nyffeler et al, 2006) following immune activation during prenatal development. These effects appear to affect specifically PV þ interneurons (Ducharme et al, 2012;Ibi et al, 2010;Piontkewitz et al, 2012), although effects on other interneuronal cell types cannot be excluded.…”

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

“…Disruption of normal fetal development (Meyer et al, 2008;Vuillermot et al, 2010), together with subsequent changes in brain maturation Piontkewitz et al, 2011;Richetto et al, 2014), may then confer increased risk of behavioral and cognitive dysfunctions in later life.…”

“…Besides post--pubertal synaptic deficits, the delayed onset of prenatal poly(I:C)--induced deficits in PPI may also involve altered functional maturation of the subcortical dopamine system Vuillermot et al, 2010), brain volumetric changes throughout adolescence (Piontkewitz et al, 2011), and altered maturation of prefrontal GABAergic systems (Richetto et al, 2014). It should also be noted that prenatal poly(I:C)--induced immune activation can lead to various behavioral and neuronal abnormalities with early juvenile or adolescent onsets, including hypersensitivity to dopamine--stimulating psychotomimetic drugs (Meyer et al, 2008,;Vuillermot et al, 2010), cognitive deficits , impairments in social interaction (Aavani et al, 2015), and deficits in hippocampal neurogenesis .…”