Timing of maternal immune activation and sex influence schizophrenia-relevant cognitive constructs and neuregulin and GABAergic pathways

Nov 22, 2021Brain, behavior, and immunity

Timing of maternal immune activation and sex affect thinking skills and specific brain chemical systems linked to schizophrenia

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Abstract

Maternal immune activation during pregnancy affects cognitive constructs relevant to schizophrenia, with timing and sex playing critical roles.

Early maternal immune activation disrupts working memory and reduces perseverative behavior specifically in female offspring.
Late maternal immune activation leads to changes in working memory and deficits in reversal learning specifically in male offspring.
Gene expression of the GABA specification marker Nkx2.1 is reduced in fetal brains from both early and late exposure to immune activation.
In adult mice, reelin expression in the hippocampus is decreased following both early and late maternal immune activation.
Neuregulin and EGF signaling pathways are initially upregulated in the fetal brain but show reductions in the adult hippocampus.
Adult male mice exposed to late maternal immune activation exhibit decreased expression of Nrg3 and reduced serine racemase levels.

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Maternal immune activation (MIA) during pregnancy is an established environmental risk factor for schizophrenia. Timing of immune activation exposure as well as sex of the exposed offspring are critical factors in defining the effects of MIA. However, the specificity of MIA on the component structure of schizophrenia, especially cognition, has been difficult to assess due to a lack of translational validity of maze-like testing paradigms. We aimed to assess cognitive domains relevant to schizophrenia using highly translational touchscreen-based tasks in male and female mice exposed to the viral mimetic, poly(I:C) (5 mg/k, i.p.), during early (gestational day (GD) 9-11) and late (GD13-15) gestational time points. Gene expression of schizophrenia candidate pathways were assessed in fetal brain immediately following poly(I:C) exposure and in adulthood to identify its influence on neurodevelopmental processes. Sex and window specific alterations in cognitive performance were found with the early window of MIA exposure causing female-specific disruptions to working memory and reduced perseverative behaviour, while late MIA exposure caused male-specific changes to working memory and deficits in reversal learning. GABAergic specification marker, Nkx2.1 gene expression was reduced in fetal brains and reelin expression was reduced in adult hippocampus of both early and late poly(I:C) exposed mice. Neuregulin and EGF signalling were initially upregulated in the fetal brain, but were reduced in the adult hippocampus, with male mice exposed in the late window showing reduced Nrg3 expression. Serine racemase was reduced in both fetal and adult brain, but again, adult reductions were specific to male mice exposed at the late time point. Overall, we show that cognitive constructs relevant to schizophrenia are altered by in utero exposure to maternal immune activation, but are highly dependent on the timing of infection and the sex of the offspring. Glutamatergic and epidermal growth factor pathways were similarly altered by MIA in a timing and sex dependent manner, while MIA-induced GABAergic deficits were independent of timing or sex.

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Timing of maternal immune activation and sex influence schizophrenia-relevant cognitive constructs and neuregulin and GABAergic pathways

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