Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation

Abstract

Maternal immune activation (MIA) is an environmental risk factor for schizophrenia, and may contribute to other developmental disorders including autism and epilepsy. Activation of pro-inflammatory cytokine systems by injection of the synthetic double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C) mediates important neurochemical and behavioral corollaries of MIA, which have relevance to deficits observed in schizophrenia. We examined the consequences of MIA on forebrain expression of neuregulin-1 (NRG-1), brain-derived neurotrophic factor (BDNF) and their receptors, ErbB4 and trkB, respectively, genes associated with schizophrenia. On gestational day 14, pregnant rats were injected with Poly I:C or vehicle. Utilizing in situ hybridization, expression of NRG-1, ErbB4, BDNF, and trkB was examined in male rat offspring at postnatal day (P) 14, P30 and P60. ErbB4 mRNA expression was significantly increased at P30 in the anterior cingulate (AC Ctx), frontal, and parietal cortices, with increases in AC Ctx expression continuing through P60. ErbB4 expression was also elevated in the prefrontal cortex (PFC) at P14. In contrast, NRG-1 mRNA was decreased in the PFC at P60. Expression of BDNF mRNA was significantly upregulated in the PFC at P60 and decreased in the AC Ctx at P14. Expression of trkB was increased in two regions, the piriform cortex at P14 and the striatum at P60. These findings demonstrate developmentally and regionally selective alterations in the expression of schizophrenia-related genes as a consequence of MIA. Further study is needed to determine contributions of these effects to development of alterations of relevance to neuropsychiatric diseases.

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

“…Animals were housed under standard conditions with access to food and water ad libitum . The Poly I:C treatment protocol was performed as previously described (Bronson et al, 2011; Hemmerle et al, 2015). Briefly, on gestational day 14 pregnant dams were injected with Poly I:C (8 mg/kg i.p.…”

“…Semi-adjacent sections were processed for the in situ hybridization localization of GAD 67 mRNA using a 35 S-labeled cDNA probe, as previously described (Seroogy and Herman, 1997; Hemmerle et al, 2012, 2015; Makinson et al, 2015). Briefly, slides were pretreated, dehydrated and delipidated prior to hybridization.…”

“…Analysis of the film autoradiograms was performed by taking densitometry measurements utilizing Scion Image software (NIH) as described previously (Numan et al, 2005; Hemmerle et al, 2012, 2015). At least six sections per area per animal were measured from the following regions: prefrontal cortex (PFC, including prelimbic, infralimbic and anterior cingulate cortex subdivisions), frontal, parietal and piriform cortices, striatum, hippocampus, and thalamus.…”

Immunoadolescence: Neuroimmune development and adolescent behavior

“…At present, we can refer to neurocircuitry development that is better understood; prefrontal fast-spiking interneurons do not mature until late adolescence (Tseng and O'Donnell, 2007), therefore the deleterious effects of immune insults to cortical function may not become evident until the transition through adolescence. Additionally, recent data have illustrated that prenatal immune activation alters the expression of genes for neurotrophic and neurodevelopmental regulators within the prefrontal cortex, but these expression changes were not seen prior to adolescence (Hemmerle et al, 2015). These findings further suggest that the effects of neuro-immune events leading to schizophrenia might manifest during a period of rapid and critical development of the prefrontal cortex.…”

Hormesis, cellular stress response and neuroinflammation in schizophrenia: Early onset versus late onset state

“…Increasing evidence supports a role of immune activation as a prominent causative factor in the pathogenesis of a number of major neuropsychiatric disorders as well (Hemmerle et al, ). Consistent with this notion, recent studies have demonstrated that the inflammasome modulates initial neuroinflammatory processes at the initial stage, with secondary events inclusive of oxidative stress that have been shown to activate the inflammasome (Kim et al, ).…”