Late prenatal immune activation in mice induces transgenerational effects via the maternal and paternal lineages.

Prenatal exposure to infectious or noninfectious immune activation is an environmental risk factor for neurodevelopmental disorders and mental illnesses. Recent research using animal models suggests that maternal immune activation (MIA) during early to middle stages of pregnancy can induce transgenerational effects on brain and behavior, likely via inducing stable epigenetic modifications across generations. Using a mouse model of viral-like MIA, which is based on gestational treatment with poly(I:C), the present study explored whether transgenerational effects can also emerge when MIA occurs in late pregnancy. Our findings demonstrate that the direct descendants born to poly(I:C)-treated mothers display deficits in temporal order memory, which are similarly present in second- and third-generation offspring. These transgenerational effects were mediated via both the maternal and paternal lineages and were accompanied by transient changes in maternal care. In addition to the cognitive effects, late prenatal immune activation induced generation-spanning effects on the prefrontal expression of gamma-aminobutyric acid (GABA)ergic genes, including parvalbumin and distinct alpha-subunits of the GABAA receptor. Together, our results suggest that MIA in late pregnancy has the potential to affect cognitive functions and prefrontal gene expression patterns in multiple generations, highlighting its role in shaping disease risk across generations.

Raymann S ，Schalbetter SM ，Schaer R ，Bernhardt AC ，Mueller FS ，Meyer U ，Weber-Stadlbauer U ... -  《-》

Transgenerational modification of dopaminergic dysfunctions induced by maternal immune activation.

Weber-Stadlbauer U ，Richetto J ，Zwamborn RAJ ，Slieker RC ，Meyer U ... -  《-》

Mouse models of maternal immune activation: Mind your caging system!

Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools to study neuronal and behavioral dysfunctions in relation to infection-mediated neurodevelopmental disorders. One of the most widely used MIA models is based on gestational administration of poly(I:C) (= polyriboinosinic-polyribocytdilic acid), a synthetic analog of double-stranded RNA that induces a cytokine-associated viral-like acute phase response. The effects of poly(I:C)-induced MIA on phenotypic changes in the offspring are known to be influenced by various factors, including the precise prenatal timing, genetic background, and immune stimulus intensity. Thus far, however, it has been largely ignored whether differences in the basic type of laboratory housing can similarly affect the outcomes of MIA models. Here, we examined this possibility by comparing the poly(I:C)-based MIA model in two housing systems that are commonly used in preclinical mouse research, namely the open cage (OC) and individually ventilated cage (IVC) systems. Pregnant C57BL6/N mice were kept in OCs or IVCs and treated with a low (1 mg/kg, i.v.) or high (5 mg/kg, i.v.) dose of poly(I:C), or with control vehicle solution. MIA or control treatment was induced on gestation day (GD) 9 or 12, and the resulting offspring were raised and maintained in OCs or IVCs until adulthood for behavioral testing. An additional cohort of dams was used to assess the influence of the different caging systems on poly(I:C)-induced cytokine and stress responses in the maternal plasma. Maternal poly(I:C) administration on GD9 caused a dose-dependent increase in spontaneous abortion in IVCs but not in OCs, whereas MIA in IVC systems during a later gestational time-point (GD12) did not affect pregnancy outcomes. Moreover, the precise type of caging system markedly affected maternal cytokines and chemokines at basal states and in response to poly(I:C) and further influenced the maternal levels of the stress hormone, corticosterone. The efficacy of MIA to induce deficits in working memory, social interaction, and sensorimotor gating in the adult offspring was influenced by the different housing conditions, the dosing of poly(I:C), and the precise prenatal timing. Taken together, the present study identifies the basic type of caging system as a novel factor that can confound the outcomes of MIA in mice. Our findings thus urge the need to consider and report the kind of laboratory housing systems used to implement MIA models. Providing this information seems pivotal to yield reproducible results in these models.

Mueller FS ，Polesel M ，Richetto J ，Meyer U ，Weber-Stadlbauer U ... -  《-》

Transgenerational transmission and modification of pathological traits induced by prenatal immune activation.

Weber-Stadlbauer U ，Richetto J ，Labouesse MA ，Bohacek J ，Mansuy IM ，Meyer U ... -  《-》

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

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.

Nakamura JP ，Schroeder A ，Gibbons A ，Sundram S ，Hill RA ... -  《-》