Baseline immunoreactivity before pregnancy and poly(I:C) dose combine to dictate susceptibility and resilience of offspring to maternal immune activation

Estes, Myka L.; Prendergast, Kathryn; MacMahon, Jeremy A.; Cameron, Scott A.; Aboubechara, John Paul; Farrelly, Kathleen; Sell, Gabrielle L.; Haapanen, Lori; Schauer, Joseph; Horta, Aurora; Shaffer, Ida C.; Le, Catherine T.; Kincheloe, Greg N.; Tan, Danielle John; List, Deborah van der; Bauman, Melissa D.; Carter, Cameron S.; Water, Judy Van de; McAllister, A. Kimberley

doi:10.1016/j.bbi.2020.04.061

Cited by 42 publications

(28 citation statements)

References 45 publications

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“…The stronger contribution of within-litter variability observed here is consistent with the findings from a recent study using the poly(I:C)-based MIA model in mice, which revealed larger within-litter than between-litter variability in the context of MIA and disruption of cortical interneuron development [60]. Hence, in addition to between-litter variability [6], factors pertaining to within-litter variability should be considered in MIA models that are implemented in litterbearing mammals such as mice. The factors determining within-litter variability in MIA models remain largely unknown and warrant further investigations.…”

Section: Discussionsupporting

confidence: 92%

“…Hence, there may be a considerable degree of resilience to MIA, which determines the extent to which offspring are protected from developing lasting abnormalities in brain functions and behavior. Several antenatal factors are emerging as elements that can promote resilience to MIA [4], including low maternal baseline immunoreactivity [6]. The latter has recently been identified in an isogenic mouse model of MIA and extends findings from epidemiological and experimental investigation suggesting that the intensity of MIA is a critical factor determining the neurodevelopmental consequences in the offspring [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 53%

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Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation

et al. 2020

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Infectious or noninfectious maternal immune activation (MIA) is an environmental risk factor for psychiatric and neurological disorders with neurodevelopmental etiologies. Whilst there is increasing evidence for significant health consequences, the effects of MIA on the offspring appear to be variable. Here, we aimed to identify and characterize subgroups of isogenic mouse offspring exposed to identical MIA, which was induced in C57BL6/N mice by administration of the viral mimetic, poly(I:C), on gestation day 12. Cluster analysis of behavioral data obtained from a first cohort containing >150 MIA and control offspring revealed that MIA offspring could be stratified into distinct subgroups that were characterized by the presence or absence of multiple behavioral dysfunctions. The two subgroups also differed in terms of their transcriptional profiles in cortical and subcortical brain regions and brain networks of structural covariance, as measured by ex vivo structural magnetic resonance imaging (MRI). In a second, independent cohort containing 50 MIA and control offspring, we identified a subgroup of MIA offspring that displayed elevated peripheral production of innate inflammatory cytokines, including IL-1β, IL-6, and TNF-α, in adulthood. This subgroup also showed significant impairments in social approach behavior and sensorimotor gating, whereas MIA offspring with a low inflammatory cytokine status did not. Taken together, our results highlight the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network, and immunological profiles even under conditions of genetic homogeneity. These data have relevance for advancing our understanding of the variable neurodevelopmental effects induced by MIA and for biomarker-guided approaches in preclinical psychiatric research.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 53%

Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation

et al. 2020

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“…We used paired transcriptomic and neuroanatomical analyses to map changes in the fetal brain following MIA in a poly(I:C) mouse model ( Figure 1 , Figure 1—figure supplement 1 , Figure 1—figure supplement 2 and Figure 1—figure supplement 3 ). Induction of MIA via poly(I:C) injection at E12.5 produces relevant phenotypes in mice ( Choi et al, 2016 ; Shin Yim et al, 2017 ; Smith et al, 2007 ) and the specific implementation of this model was recently validated in our hands to produce sufficient levels of MIA to mimic viral infection and cause aberrant behavioral outcomes in offspring ( Estes et al, 2020 ). The dosage of 30 mg/ml poly(I:C) elicited substantial elevations in maternal serum IL-6 (on average 2200 pg/ml) 4 hr following injection ( Figure 1—figure supplement 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…IL-6 serum levels were measured at 2.5 hr post-injection. Temperature, weight, and sickness behavior were tracked as previously described ( Estes et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

“…Maternal Immune Activation. Assessment of females baseline immunoreactivity before pregnancy and maternal immune activation were performed as previously described (Estes et al, 2020). Since female mice display a wide range of baseline immunoreactivity to poly(I:C) that dictates susceptibility and resilience of offspring from later pregnancies to MIA, virgin females in the lowest 25 th percentile of immune responsiveness to poly(I:C) (IL-6 serum levels) were excluded from the study to reduce variability and ensure sufficient immune responsiveness of all included dams.…”

Section: Consistent With Links Between Ndds and Developmental Timingmentioning

confidence: 99%

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Sequential perturbations to mouse corticogenesis following in utero maternal immune activation

Canales

Estes

Cichewicz

et al. 2021

eLife

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In utero exposure to maternal immune activation (MIA) is an environmental risk factor for neurodevelopmental and neuropsychiatric disorders. Animal models provide an opportunity to identify mechanisms driving neuropathology associated with MIA. We performed time course transcriptional profiling of mouse cortical development following induced MIA via poly(I:C) injection at E12.5. MIA-driven transcriptional changes were validated via protein analysis, and parallel perturbations to cortical neuroanatomy were identified via imaging. MIA-induced acute upregulation of genes associated with hypoxia, immune signaling, and angiogenesis, by six hours following exposure. This acute response was followed by changes in proliferation, neuronal and glial specification, and cortical lamination that emerged at E14.5 and peaked at E17.5. Decreased numbers of proliferative cells in germinal zones and alterations in neuronal and glial populations were identified in the MIA-exposed cortex. Overall, paired transcriptomic and neuroanatomical characterization revealed a sequence of perturbations to corticogenesis driven by mid-gestational MIA.

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Sources and Translational Relevance of Heterogeneity in Maternal Immune Activation Models

Meyer

2022

Current Topics in Behavioral Neurosciences

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The epidemiological literature reporting increased risk for neurodevelopmental and psychiatric disorders after prenatal exposure to maternal immune activation (MIA) is still evolving, and so are the attempts to model this association in animals. Epidemiological studies of MIA offer the advantage of directly evaluating human populations but are often limited in their ability to uncover pathogenic mechanisms. Animal models, on the other hand, are limited in their generalizability to psychiatric disorders but have made significant strides toward discovering causal relationships and biological pathways between MIA and neurobiological phenotypes. Like in any other model system, both planned and unplanned sources of variability exist in animal models of MIA. Therefore, the design, implementation, and interpretation of MIA models warrant a careful consideration of these sources, so that appropriate strategies can be developed to handle them satisfactorily. While every research group may have its own strategy to this aim, it is essential to report the methodological details of the chosen MIA model in order to enhance the transparency and comparability of models across research laboratories. Even though it poses a challenge for attempts to compare experimental findings across laboratories, variability does not undermine the utility of MIA models for translational research. In fact, variability and heterogenous outcomes in

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Baseline immunoreactivity before pregnancy and poly(I:C) dose combine to dictate susceptibility and resilience of offspring to maternal immune activation

Cited by 42 publications

References 45 publications

Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation

Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation

Sequential perturbations to mouse corticogenesis following in utero maternal immune activation

Sources and Translational Relevance of Heterogeneity in Maternal Immune Activation Models

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