Neurodevelopmental Resilience and Susceptibility to Maternal Immune Activation

Trends in Neurosciences Series: Long-lasting Impact of Early-Life Stress and Adversity

Review

Neurodevelopmental Resilience and Susceptibility to Maternal Immune Activation Urs Meyer1,2,* Maternal immune activation (MIA), be it triggered by infectious or noninfectious stimuli, is implicated in various psychiatric and neurological disorders with developmental etiologies. Its consequences on the offspring’s mental health are heterogeneous and influenced by a number of factors shaping the specificity and/or severity of pathological outcomes. There is also a substantial degree of resilience to MIA, which determines the extent to which offspring are protected from developing neurodevelopmental sequelae. This review provides a synopsis of the plausible sources that account for the heterogeneous outcomes of MIA and discusses key factors that are critical for establishing neurodevelopmental resilience and susceptibility to this early-life adversity.

Prenatal Programming of Brain Disorders by MIA Physiological disturbances compromising the quality of fetal development and growth can affect developmental trajectories in a manner that predisposes the offspring to chronic diseases. Such early-life programming is increasingly recognized to play a critical role in the etiology of various psychiatric and neurological disorders, including intellectual disability, autism spectrum disorder (ASD), schizophrenia, bipolar disorder, microcephaly, and cerebral palsy [1,2]. One commonality between these disorders is that the underlying pathological processes start during fetal development [3,4]. Furthermore, they share considerable numbers of environmental risk factors and molecular pathways of transcriptional dysregulation [5,6]. These findings have led to the proposal that these disorders lie along a continuum of neurodevelopmental causalities, wherein the genetic architecture and environmental context determines the specificity of the eventual pathological outcomes [4,7]. MIA during pregnancy, be it in response to infections or to noninfectious stimuli such as maternal allergic asthma, toxin exposures, stress, or obesity, is one of the environmental risk factors of psychiatric and neurological disorders with neurodevelopmental etiologies [6,8–10]. While MIA has long been implicated in schizophrenia and ASD [11,12], the recent outbreak of Zika virus and its association with microcephaly has greatly increased the awareness of the possible neurodevelopmental sequelae of MIA [13]. A number of pathophysiological processes can contribute to the association between MIA and neurodevelopmental disorders, including inflammatory processes and oxidative stress occurring in maternal and fetal compartments, activation of maternal stress response systems such as the hypothalamic–pituitary–adrenal (HPA) axis, temporary micro- and/or macronutrient deficiencies, and disruption of placental functions [14,15]. Some of the effects of MIA on psychiatric and neurological disorders are influenced by fetal sex [16–18], emphasizing that the vulnerability to MIA can differ between male and female offspring. Despite the increasing evidence for significant health consequences, however, the effects of MIA on the offspring are heterogeneous in both sexes (Figure 1). While some offspring of MIA-exposed mothers develop central nervous system (CNS) disorders, a substantial portion does not [8,19] (Figure 1). This dichotomy becomes obvious when considering that maternal infections or exposures to noninfectious immunopathologies are relatively common during pregnancy. For example, the prevalence of respiratory tract infections is estimated to be as high as 50% during pregnancy, while febrile episodes and urinary tract infections occur in approximately 17–21% of pregnant women [20]. Likewise, allergic diseases affect approximately 18–30% of women of childbearing age [21], with asthma accounting for approximately 4–8% of these cases [22]. Despite their relatively high prevalence,

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Highlights Maternal immune activation (MIA) during pregnancy is increasingly recognized as an etiological risk factor for various psychiatric and neurological disorders. Whereas a substantial portion of offspring is resilient to the consequences of MIA, susceptible offspring may develop overt physical, neurological, and/or mental disorders. Various factors can promote susceptibility to the effects of MIA, including maternal hypoferremia and anemia, gestational diabetes mellitus, maternal stress during pregnancy, dysbiosis of the maternal gut microbiota, peripubertal exposure to psychological trauma, and chronic cannabis use during periadolescence. Factors that can promote resilience to the effects of MIA include high maternal status for vitamin D, iron, zinc, or choline, efficient anti-inflammatory and antioxidant response systems, and the availability of omega-3 fatty acids.

1Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland 2Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland

*Correspondence: [email protected]

https://doi.org/10.1016/j.tins.2019.08.001 ª 2019 Elsevier Ltd. All rights reserved.

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Figure 1. Pathways of Neurodevelopmental Resilience and Susceptibility to Maternal Immune Activation. Maternal immune activation during pregnancy, be it induced by infectious or noninfectious stimuli, has variable effects on the offspring. Whereas a substantial portion of offspring are resilient to maternal immune activation and do not acquire overt pathologies, neurodevelopmental sequelae occur in susceptible offspring. The neurodevelopmental consequences among the latter are heterogeneous and can span a range of neurological and psychiatric disorders with varying temporal onsets (as indicated by the corresponding lengths of the arrows and the broken-lined circles). Note that the illustrated pathways among susceptible offspring represent risks but not deterministic relationships.

however, infectious and noninfectious immunopathologies cause lasting CNS disorders in only a small portion of exposed offspring [8,15,23–25]. Hence, there is a substantial degree of resilience to MIA, which determines the extent to which offspring are protected from neurodevelopmental sequelae. This review provides a synopsis of the plausible sources that account for the heterogeneous outcomes of MIA and discusses key factors that are critical for establishing neurodevelopmental resilience and susceptibility to this early-life adversity (Figure 2, Key Figure).

Heterogeneity of the Effects of MIA As reviewed elsewhere [6,8–10,26], prenatal exposure to a variety of viral, bacterial, and protozoan infections has been associated with increased risk of psychiatric and neurological disorders with neurodevelopmental etiologies. These findings have led to the hypothesis that common immunological factors in general, and inflammatory mediators in particular, are responsible for the disruption of fetal brain development following maternal infection [27,28]. Since the initial formulation of this hypothesis by Gilmore and Jarskog in 1997 [29], extensive epidemiological research and translational work in animal models of MIA have underscored a critical role for cytokine-associated inflammatory events in this association. In human epidemiological studies, for example, elevated maternal levels of various proinflammatory markers, including interleukin (IL)-1a, IL-6, IL-8, interferon-gamma (IFN-g), tumor necrosis factor alpha (TNF-a), granulocyte macrophage colony-stimulating factor (GMCF), and C-reactive protein (CRP), were found to increase the risk of schizophrenia and ASD [8,18,25]. Significant associations between increased levels of maternal cytokines and neurodevelopmental disturbances have also been identified in studies that cross current nosological boundaries. For example, recent

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Key Figure

Factors Promoting Neurodevelopmental Resilience and Susceptibility to Maternal Immune Activation

Figure 2. The illustration summarizes the known factors that can promote resilience (blue) or susceptibility (red) to maternal immune activation. Note that some factors operate at prenatal and perinatal stages, whereas others act during postnatal stages of life.

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human studies focusing on IL-6 found that the maternal levels of this cytokine correlated with altered connectivity of the amygdala in newborns [30,31] and with variation in the frontolimbic white matter [32] and alterations in the cognitive development of toddlers [30–32]. Because it is unlikely that associations between biomarkers of inflammation during pregnancy are accounted for by one or a small group of infections [33], these findings may indeed point to a ‘common pathogenic pathway’ by which different infections or noninfectious immunopathologies give rise to CNS anomalies in the offspring. A plethora of findings derived from animal models, in which MIA is induced by noninfectious immunogens (Table 1), readily supports this notion. As reviewed extensively elsewhere [8,9,34], these noninfectious MIA models revealed various behavioral, cognitive, neuroanatomical, and molecular abnormalities relevant to major psychiatric disorders with neurodevelopmental origins. Moreover, they have contributed to our understanding of how specific cytokines, including IL-1b, IL-6, and IL17A, can mediate the association between MIA and long-term pathology in the offspring under stringent experimental conditions [35–37]. Despite the evidence supporting a common pathogenic pathway for MIA, however, this pathogenesis model appears to be an oversimplification for various reasons. As discussed below, some pathogenic pathways differ intrinsically between distinct forms of MIA, and in turn these differences are likely to account for a substantial portion of the heterogeneity of the neurodevelopmental effects induced by MIA.

Specificity of MIA: Vertical Transmission of Pathogens The specificity of the infectious pathogen may account for a substantial portion of the heterogeneous neurodevelopmental sequelae induced by MIA and may influence the effect size of associations between prenatal infections and risk of psychiatric disorders. Some pathogens may directly impact the developing offspring through their capacity for vertical transmission; that is, the passage from mother

Immunogen

Infectivity

Principal mode of action

Refs

IL-6

No

Induction of fever, acute-phase responses, and IL-17A expression after systemic maternal

[35]

administration Imiquimod

No

Recognition by TLR7 and induction of cytokine-associated acute-phase response to single-stranded

[44]

RNA (viral or bacterial) after systemic maternal administration Influenza virus

Yes

Broad innate and adaptive antiviral immune response, including maternal production of cytokines and

[8,41,114]

antibodies, and activation of B and T cells after maternal intranasal infection LPS

No

Recognition by TLR4 and induction of cytokine-associated bacterial-like acute-phase response after

[36,41,43]

systemic maternal administration Ovalbumin

No

(primed) Poly(I:C)a

Induction of polarized TH2 immune responses, including increased maternal production of IL-4 and IL-5

[115,116]

and variable secretion of IL-1b, IL-6, TNFa, and IL-17A No

Recognition by TLR3 and induction of cytokine-associated viral-like acute-phase response to double-

[34,41,52,53]

stranded RNA after systemic maternal administration Staphylococcal

No

Maternal activation and proliferation of CD4+ T cells and T cell-derived cytokine production

[45]

Yes

Variable IFNg-guided innate and adaptive immune responses in the maternal host; vertical

[8,13,101]

enterotoxin Toxoplasma gondii Turpentine

transmission, infection of fetuses, and induction of congenital toxoplasmosis No

Local tissue damage, recruitment and activation of immune cells, and secretion of proinflammatory

[67]

cytokines after maternal intramuscular injection Zika virus

Yes

Type I IFN-guided innate and cell-mediated and humoral adaptive immune responses in the maternal host; vertical transmission and infection of fetuses

Table 1. Overview of the Diverse Types of Immunogens Used in Animal Models of MIA Abbreviation: Poly(I:C), polyriboinosinic:polyribocytidylic acid.

a

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to fetus/baby across the placenta, through perinatal contact, or in breast milk. Known examples of pathogens showing vertical transmission are Toxoplasma gondii, rubella virus, cytomegalovirus (CMV), and herpes simplex viruses (HSVs), which are commonly referred to as the TORCH agents [13]. Another important example is Zika virus, which is similarly able to cross the placental barrier and infect the fetus directly [13]. Maternal exposure to TORCH agents or Zika virus can cause severe fetal or neonatal outcomes, including spontaneous abortion, stillbirth, and/or teratogenicity such as congenital heart disease, cerebral malformations, blindness and deafness, and intellectual disability [13,33]. Two illustrative examples of the teratogenic effects induced by vertically transmitted infections are microcephaly and the congenital rubella syndrome, which are caused by maternal gestational infection with Zika virus or rubella virus, respectively. In addition, maternal exposure to some of the TORCH agents was found to increase offspring’s risk of developing psychiatric disorders later in life [6,8,11,38,39]. The effect sizes of associations between prenatal infections with TORCH agents and risk of psychiatric disorders appear to be larger than those associated with prenatal exposure to nontransmitted infections [8,11,12,38–40]. This difference should, however, be interpreted with caution, given that the existing epidemiological studies of prenatal infections used IgG titers and/ or seropositivity as a proxy for ascertaining maternal infections, rather than assessing acute infections during pregnancy and following up long-term outcomes in the offspring. While prenatal exposure to vertically nontransmittable infections such as influenza virus can still impose a risk for the offspring to develop psychiatric disorders later in life [8,12,19,23,40], severe physical and neurological sequelae are typically not seen after these types of infections. Even in the absence of vertical transmission of pathogens, infections during pregnancy induce a number of post-acute pathophysiological processes in the maternal, placental, and fetal compartments. As reviewed in detail elsewhere [14,15], these responses include the production of soluble immune factors such as cytokines and other mediators of inflammation, the generation of reactive oxygen species, and the activation of maternal stress response systems such as the HPA axis and subsequent release of stress hormones. Some of these factors can cross the placental barrier and enter the fetal environment, thereby causing fetal inflammation, oxidative stress, and endocrine anomalies. Maternal infection during pregnancy can further induce inflammatory responses in the placenta and cause placental insufficiency, which in turn can cause fetal hypoxemia. In addition, infection can cause (temporary) states of macronutrient and micronutrient deficiency, which limits the fetal availability of essential nutrients necessary for normal fetal development and growth. Finally, maternal infection during pregnancy can modify the microbial composition of the placenta, which might alter the development of the offspring’s microbiome. All of these post-acute pathophysiological processes can contribute to the disruption of normal fetal brain development, but their long-term neurodevelopmental effects are likely to depend on intricate interactions between individual components of the post-acute response, maternal physiology, and genetic influences (Figure 2).

Specificity of MIA: Immune Mediators The specificity of the maternal immune response, be it triggered by infectious or noninfectious stimuli, appears to shape the nature and/or severity of the pathological consequences on brain functions and behavior in the offspring as well. This notion is supported by recent findings from animal models of MIA showing that maternal activation of distinct subtypes of toll-like receptors (TLRs) (Box 1) leads to differential outcomes in the offspring. As reviewed elsewhere [34,41], most current MIA models are based on agents that activate the TLR3 or TLR4 subtypes, which leads to an innate immune response typically occurring early after infection with viruses or bacteria, respectively. Prenatal exposure to these immunogens induces a partially overlapping spectrum of brain and behavioral anomalies in animal models [34,41]. There are, however, some notable differences between the pathological outcomes of prenatal exposure to TLR3 or TLR4 agonists. For example, whereas prenatal activation of TLR3 in rats and mice leads to cellular, neurochemical, and behavioral phenotypes that are characteristic of a hyperdopaminergic state [42], prenatal activation of TLR4 was found to induce a hypodopaminergic state instead [43]. More recently, Missig et al. [44] found that prenatal activation of the TLR7 subtype in mice induced phenotypic changes that are readily distinguishable from (and in some ways opposite to) those seen following prenatal activation of TLR3 and/or TLR4. Likewise, activation of

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maternal T cells through bacterial superantigens leads to post-acute maternal immune reactions and phenotypic changes in the offspring that are distinct from those induced by prenatal exposure to TLR3 or TLR4 agonists [45]. These findings thus suggest that different immunogens can induce a distinct set of neuroimmune abnormalities across brain development and divergent long-term changes in brain structure and function, even if they are of a noninfectious nature. Akin to the recent discoveries in animal models [41–45], differences in the combination of inflammatory mediators may account for the variable and equivocal associations in epidemiological studies assessing the role of maternal inflammation in psychiatric disorders [25,46–49]. The ambivalent roles of maternal IL-17A and CRP in the etiology of ASD are timely examples illustrating this conundrum. Whereas increased maternal IL-17A and CRP levels are associated with ASD traits in mouse models of MIA and some human studies [37,48], other studies find no association of these inflammatory markers with ASD risk or even indicate a protective role for them [46,47,49].

Intensity of MIA There is currently insufficient human epidemiological data to draw firm conclusions on what level of MIA intensity should be considered a risk factor for neurodevelopmental and psychiatric disorders. The current assumption is, however, that MIA at high intensity has a more extensive impact on the offspring’s mental and physical health than milder forms of MIA. A number of studies show a positive correlation between the magnitude of maternal inflammation during pregnancy and anomalies in various neuroanatomical, behavioral, and cognitive indices in the general population [30–32] and in cases with schizophrenia [50]. Likewise, the risk of ASD after prenatal exposure to maternal fever has been found to increase dose dependently [24,51]. Similar dose-dependent effects were identified in animal models of MIA [52,53], which allow the dissection of subthreshold and suprathreshold effects of MIA on brain development and functions under stringent experimental conditions. If confirmed by future epidemiological studies and basic research, these findings would indicate that the intensity of MIA determines the extent of risk of the exposed offspring for developing CNS abnormalities (Figure 2).

Timing of MIA Maternal infection with TORCH pathogens is known to produce varying pathological outcomes depending on the gestational timing of exposure [13,38]. Maternal exposure to TORCH pathogens typically causes severe neurodevelopmental and neurological anomalies when occurring during the first half of pregnancy. By contrast, TORCH infections during later gestational stages are associated with more subtle and localized neuropathology in the offspring, but still impose a risk for congenital infections of the newborn and/or chronic mental illnesses later in life. Hence, the prenatal timing of vertically transmitted infections is an important factor influencing the offspring’s susceptibility to lasting neurological deficits.

Box 1. TLRs and Their Ligands TLRs are a family of membrane-spanning noncatalytic receptors that play key roles in the innate immune system. They are expressed on sentinel immune cells such as macrophages and dendritic cells, with additional expression found in nonimmune cells such as fibroblasts and trophoblasts [109]. TLRs recognize pathogenassociated molecular patterns (PAMPs) derived from various microbes, including viruses, bacteria, and protozoans. On binding of PAMPs, TLRs signal through the recruitment of specific adaptor molecules, leading to the activation of multiple transcription factors, such as NF-kB and the IFN regulatory factor (IRF) family of transcription factors [109]. Activation of these transcription factors eventually results in the production of numerous immune mediators, including proinflammatory cytokines and chemokines. Thus far, ten subtypes of TLR (TLR1– TLR10) have been identified in humans, all of which are evolutionary conserved across numerous species [109]. Distinct TLR subtypes recognize distinct PAMPs and stimulate the production of a defined array of immune mediators. For example, while TLR4 recognizes lipopolysaccharide (LPS) expressed on Gram-negative bacteria, TLR3 and TLR7 recognize double-stranded and single-stranded RNA, respectively [109].

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There may also be timing-dependent effects of MIA on psychiatric disease risk, but this hypothesis warrants further examination. Birth cohort studies that use prospectively acquired serological biomarkers of infection or inflammation in individual pregnancies tend to suggest that MIA in the first half of pregnancy has larger effects on the risk of developing psychotic or externalizing disorders compared with exposure in the second half of pregnancy [18,39,54,55]. Some epidemiological studies similarly report trimester-dependent effects on MIA on ASD risk [24,56], although mixed results exist in this regard [23,57,58]. An inherent limitation of the majority of existing epidemiological studies is that stratification of MIA by trimester reduces the statistical power, such that larger sample sizes would often be needed to ascertain trimester-dependent effects [8]. The use of animal models, in which MIA can be precisely timed according to specific stages of pregnancy, provides a unique opportunity to complement the epidemiological research on trimester-specific effects of MIA [8,34,41]. In this context, it should also be pointed out that while the present discussion focuses on prenatal exposure to MIA and its neurodevelopmental consequences, infections and immune dysregulation across the postnatal life span are risk factors for mental illnesses as well [59]. As reviewed elsewhere [28,60], infections and immune dysregulation not only affect brain development but may also trigger cognitive and psychiatric symptoms in the mature brain after invasion of the brain parenchyma or through indirect effects induced by brain-reactive antibodies and/or systemic inflammatory processes.

Prenatal Factors Promoting Resilience or Susceptibility Maternal Micronutrients Essential vitamins and minerals, which are typically referred to as micronutrients, are dietary components required in small quantities to support a range of physiological functions throughout life, including antenatal life [61]. They are pivotal for optimal pregnancy outcomes and regulate virtually every biological and metabolic process necessary for fetal development and growth. While micronutrient deficiencies per se have been implicated in abnormal CNS development [40,62], some micronutrients can critically determine the extent to which offspring are resilient or susceptible to MIA (Figure 2). Important examples of the latter are iron, zinc, vitamin D, omega-3, folic acid, and choline. Not only are they essential for normal fetal development [40,42,62], but they also establish resistance to infection and optimal immune functioning [63]. Maternal micronutrient deficiencies such as hypoferremia and omega-3 deficiency exacerbates the neurodevelopmental sequelae of MIA [64–66] and, conversely, high maternal status for iron, zinc, vitamin D, or choline attenuates or even prevents the negative effects of MIA on brain development and functions in the offspring [42,67–69]. While the precise mechanisms underlying these interactions require further exploration, these findings emphasize that optimal micronutrient status during pregnancy can establish resilience to MIA (Figure 2).

Gestational Diabetes Mellitus Gestational diabetes mellitus (GDM) is the most common metabolic disorder during pregnancy and can cause considerable complications for both mother and child [70]. GDM is also a recognized risk factor for neurodevelopmental disorders and chronic mental illnesses, including ASD and schizophrenia [71,72]. While the core metabolic characteristics of GDM are hyperglycemia and hyperinsulinemia, this condition also leads to chronic low-grade inflammation and can amplify proinflammatory responses to infectious and noninfectious stimuli [72]. Accordingly, co-occurring MIA and GDM can potentiate each other and induce synergistic effects on brain development (Figure 2), as recently demonstrated in a seminal study using a preclinical mouse model [73]. In this study, the authors showed that GDM (induced by chronic high-fat-diet exposure before and during gestation) and MIA (induced by gestational administration of a viral mimetic) each altered inflammatory and transcriptional profiles during fetal development. Notably, the combination of GDM and MIA heightened the maternal inflammatory state and gave rise to novel, more pronounced transcriptional alterations in the fetal brain. Similar combinatorial effects await confirmation by human epidemiological studies, which could examine, for instance, whether increased body mass index (BMI) before and/or during pregnancy, and the associated pathophysiological changes such as GDM, modulates the effects of MIA on the offspring.

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Maternal Stress Maternal stress has long been implicated in the etiology of neurodevelopmental disorders [1,2,74]. This association is influenced by fetal sex [75,76], emphasizing that the neurodevelopmental susceptibility to maternal stress differs between male and female offspring. While the (sex-dependent) effects of maternal stress are likely to involve a multitude of mediating factors, inflammatory processes have emerged as an important intermediary between this early-life adversity and neurodevelopmental abnormalities in the offspring [77,78]. Moreover, maternal stress can act as a moderator in the association between MIA and neuropsychiatric risk in the offspring [79]. A striking example supporting this notion stems from recent human epidemiological studies, which demonstrated that maternal infection was not associated with depressive symptoms in adolescent offspring if maternal stress was not present during pregnancy [79]. The interaction of maternal stress with MIA may help to explain the variability in outcomes following maternal infection during pregnancy and suggests that prenatal exposure to stress can increase the neurodevelopmental susceptibility to MIA (Figure 2).

Maternal Gut Microbiome A growing number of studies highlight the importance of the gut microbiome in health and disease, including brain development, behavior, and psychiatric disorders [80]. A novel role for the microbiome has also been recognized in the context of MIA. Studies conducted in mouse and ferret models show that MIA leads to permanent changes in the gut microbiome and associated gastrointestinal abnormalities, which in turn contribute to the manifestation of behavioral dysfunctions in MIA-exposed offspring [81–83]. Moreover, initial evidence from mouse models suggests that the maternal gut microbiome modulates, or perhaps even mediates, some of the effects of MIA on brain development and functions [84,85]. In these animal models, the underlying mechanisms by which the maternal gut microbiome governs the effect on offspring brain development involve intestinal bacteria that promote T helper 17 (TH17) cell differentiation and subsequent production of IL-17A. While the clinical relevance of these findings requires confirmation in human settings, they suggest that a microbiome-driven shift towards enhanced maternal TH17 activity and IL-17A production renders the offspring more susceptible to the neurodevelopmental effects of MIA (Figure 2). Differences in the maternal gut microbiome may also be one of the various factors that are responsible for variability in animal models of MIA (Box 2).

Postnatal Factors Promoting Resilience or Susceptibility Whereas some forms of MIA cause neurodevelopmental sequelae that are immediately manifested in newborns (e.g., congenital rubella syndrome, microcephaly), others can induce latent pathological effects, the unmasking of which requires additional factors acting during postnatal development. Hence, MIA can act as an early vulnerability factor or ‘disease primer’, which can establish a metaplastic state increasing the offspring’s sensitivity to the disrupting effects of postnatal stressors. The interaction between MIA and peripubertal exposure to stress in mouse models is an illustrative example of this scenario [86,87]. This environmental ‘two-hit’ model shows that on combined exposure to two environmental risk factors, which have each been associated with increased risk of psychiatric disorders, they act in synergy to induce psychosis-related neural and behavioral abnormalities in adult mice. The clinical relevance of this concept was also confirmed by a large, population-based epidemiological study, which comprised nearly 1 million Danish people born between 1980 and 1998 [88]. This study showed that combined exposure to prenatal infection and peripubertal psychological trauma led to a significantly higher risk of adult schizophrenia than exposure to either risk factor alone. In a similar vein, the combination of MIA and periadolescent cannabinoid exposure was found to cause more extensive alterations of transcriptional networks in the adult rat brain than either exposure alone [89]. Although such interactive effects still require confirmation by human epidemiological studies, these findings suggest that chronic cannabis use during periadolescence could magnify the effects of MIA. Given that periadolescent cannabinoid exposure itself has been widely implicated as a risk factor for psychotic disorders [90], the exploration of the mechanisms underlying the putative interactions between MIA and periadolescent cannabinoid exposure appears highly warranted. Recent findings derived from animal models of periadolescent exposure to delta-9-tetrahydrocannabinol

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Box 2. Variability in Animal Models of MIA Animal models of MIA are increasingly used as experimental tools to study neurobehavioral and molecular dysfunctions in relation to immune-mediated neurodevelopmental disorders and mental illnesses. With their increasing use, however, MIA models were also destined to face increasing variability across different research laboratories. As reviewed elsewhere [34,110], a number of methodological factors can influence the severity and/or specificity of outcomes in MIA models. Many of these factors, including the choice of animal species, the genetic background of the animals, and the type of immunogen, are inherent characteristics of the experimental design. These factors often depend on the specific research questions to be addressed and thus represent planned or ‘a priori’ sources of variability [34]. For example, comparing the effects of MIA in different species allows an examination of species-specific effects, whereas the use of different types of immune-activating agents enables researchers to compare the effectiveness of different immunogens in altering brain and behavioral development. Substantial variability can also arise from unplanned or unintentional factors. Because these are identifiable only once the primary readouts of interest (e.g., behavioral phenotypes) have been collected and analyzed, this type of variability has been referred to as ‘a posteriori variability’ [34]. The precise sources underlying a posteriori variability are often less obvious than those underlying a priori variability and therefore their identification requires systematic investigation. However, with the increasing use of MIA models, along with the resulting challenges in comparing findings across laboratories, a number of factors contributing to a posteriori variability have been identified [34]. These include variability in the immunogenicity of different batches and/or vendor-specific variations of immunogens [111,112], differential susceptibility of isogenic animals obtained from different breeding facilities due to varying microbial compositions [84], and influences of the precise type of caging system [53]. To fully appreciate and deal with model variability, researchers in the field are now strongly encouraged to adhere to reporting guidelines to improve the rigor, reproducibility, and transparency of animal models of MIA [110]. While there are multiple strategies for minimizing variability in these models [34], variability per se is not an undermining characteristic of MIA models. It offers unique opportunities for new (and sometimes unexpected) discoveries, granted that researchers are aware of the potential sources of variability and are open to novel methodological approaches and ways of data acquisition and/or analysis [34]. For example, identifying susceptible and resilient mothers and/or offspring, and unraveling the mechanisms underlying this differentiation, would necessitate the use of relatively large numbers of litters and whole-litter testing approaches. Furthermore, the identification of pathological entities that go beyond predefined treatment groups requires advanced statistical methods, such as clustering approaches, principal component analyses, and perhaps even machine learning. The latter offers a powerful and unbiased approach in many areas of research [113], which often entail diverse, complex, and high-dimensional data sets exhibiting nonlinear dependencies and unknown interactions across multiple variables. Hence, although challenging in some contexts, variability in animal models of MIA can be inspiring for this rapidly growing research field.

(THC), the main psychoactive component of cannabis, points towards a possible involvement of the neuroimmune system in these interactions. For example, chronic THC exposure during periadolescence was found to induce complex and age-dependent alterations in proinflammatory cytokine signaling and microglia activation [91,92] and to negatively affect synaptic and cognitive functions via inflammatory pathways involving the activation of nuclear factor ‘kappa-light-chain enhancer’ of activated B cells (NF-kB) and cyclooxygenase-2 (COX-2) [93,94]. Hence, periadolescent cannabinoid exposure may unmask latent neuroinflammatory abnormalities induced by MIA, similar to what has been proposed for the abovementioned interactions between MIA and peripubertal exposure to psychological trauma [86,87] (Figure 2). Some postnatal factors may also promote resilience to brain dysfunctions after prenatal exposure to MIA. A known example from rodent models of MIA is dietary supplementation with omega-3 polyunsaturated fatty acids (PUFAs) during postnatal maturation, which was found to prevent the adult emergence of a number of behavioral, neurochemical, and neuroepigenetic abnormalities in MIAexposed offspring [95,96]. While the putative therapeutic or preventive potential of omega-3-PUFA diets remains controversial in the treatment of major psychiatric disorders [97], the aforementioned preclinical findings nevertheless suggest that this dietary intervention may have resilience-promoting properties in the context of MIA-induced brain pathologies (Figure 2).

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Role of Familial History and Genetic Background Genome-wide association studies (GWASs) demonstrate that there is a substantial genetic contribution to the majority of neurodevelopmental disorders [4,5,98]. Several genes identified from these studies, including those in the MHC locus and complement C4 [99], encode proteins that play important roles in immune functioning and neurodevelopment. With the exception of rare copy number variants [100], mutations in individual genes are generally associated with relatively small increases in the odds of neurodevelopmental disorders, but are hypothesized to confer larger disease susceptibility by interacting with environmental exposures, including MIA [40,101]. It is also noteworthy that the assessment of MIA exposures is sometimes required to detect genetic effects, as demonstrated, for example, by genetic association studies of schizophrenia incorporating maternal exposure to CMV infection [102,103]. Hence, environmental factors, such as MIA, can unmask the (statistical and biological) significance of certain genetic variations in neurodevelopmental disorders. The genetic background is also a plausible factor determining the extent to which offspring are susceptible or resilient to the neurodevelopmental effects of MIA. For example, epidemiological studies using familial history or maternal diagnosis of psychiatric disorders as a proxy for genetic predisposition show synergistic interactions with MIA in the causation of schizophrenia [104,105]. Interestingly, common genetic risk for schizophrenia, as indexed by the polygenic risk score (PRS), does not interact with infections in modifying the disease risk, nor does PRS predict the risk of acquiring infections before the onset of schizophrenia [106]. These recent findings have two important implications. First, while genetic liability towards infections in people with schizophrenia may exist [107], this liability is unlikely to be mediated by risk alleles and genetic loci contained in the PRS for schizophrenia [106]. Second, these PRS risk alleles and genetic loci do not appear to mediate the interactive effects between MIA and genetic susceptibility to schizophrenia, suggesting that genetic risk factors distinct from those included in the PRS may be more relevant for these interactions. While certain genetic factors can promote susceptibility to MIA [101], others can have protective effects and establish resilience instead. Polymorphism in the promoter region of IL-10, a multifunctional cytokine with strong anti-inflammatory properties [108], is an illustrative example of the resiliencepromoting effects of some genetic factors. Genetic variants of the IL-10 promoter causing increased IL-10 production can protect offspring from the neurodevelopmental sequelae of MIA, likely by enhancing the resolution of fetal brain inflammation [108].

Concluding Remarks and Future Perspectives MIA triggered by infectious or noninfectious stimuli is implicated in various psychiatric and neurological disorders with developmental etiologies. Its consequences on the offspring’s health are, however, variable and influenced by a number of factors shaping the nature and/or severity of pathological outcomes. A substantial portion of offspring is resilient to MIA and does not acquire overt pathologies. Several antenatal factors, including high maternal status for vitamin D, iron, zinc, omega-3 fatty acids, and choline, are emerging as elements that can promote resilience to MIA. By contrast, various factors acting at prenatal or postnatal stages of life can promote susceptibility to MIA, including maternal hypoferremia and anemia, GDM, maternal stress, dysbiosis of the maternal gut microbiota, peripubertal exposure to psychological trauma, and chronic cannabis use during periadolescence. Genetic factors can promote resilience or susceptibility, either through their influence on host defense and immunity or by concurrently affecting neurodevelopmental programs independent of MIA. Hence, the extent to which offspring develop neurodevelopmental sequelae of MIA or are protected from them depends on the intricate interaction between multiple environmental and genetic factors. While the importance of susceptibility and resilience factors in the context of MIA is increasingly recognized, the underlying cellular and molecular mechanisms remain elusive and warrant further investigation (see Outstanding Questions). The identification of mechanisms mediating resilience to MIA holds promise for establishing interventions that could lead to partial or full protection against the neurodevelopmental sequelae of MIA. Transdisciplinary approaches involving epidemiology and

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basic science, in which the clinical relevance of resilience factors is ascertained concurrently with the investigation of the underlying mechanisms, will help in achieving this goal. The existing diversity of animal models, in which the maternal immune system can be activated by distinct immunogens (Table 1), offers a unique opportunity for the future exploration of susceptibility and resilience factors under diverse conditions of MIA. To fully appreciate and approach this complexity, the field would readily benefit from a revival and extension of experimental approaches that make use of prenatal exposure to both infectious and noninfectious agents, rather than solely focusing on the standardization of one particular model system [8]. A closer examination of the commonalities and differences between the mediating factors and outcomes of distinct MIA conditions can help to identify the critical pathways mediating neurodevelopmental resilience and susceptibility to MIA.

Acknowledgments The author receives financial support from the Swiss National Science Foundation (grant no. 310030_169544), Boehringer Ingelheim Pharma GmbH and Co, and Wren Therapeutics Ltd. The author thanks Tina Notter for the helpful and constructive comments on the manuscript. References 1. O’Donnell, K.J. and Meaney, M.J. (2017) Fetal origins of mental health: the developmental origins of health and disease hypothesis. Am. J. Psychiatry 174, 319–328 2. Bale, T.L. (2015) Epigenetic and transgenerational reprogramming of brain development. Nat. Rev. Neurosci. 16, 332–344 3. Levitt, P. and Veenstra-VanderWeele, J. (2015) Neurodevelopment and the origins of brain disorders. Neuropsychopharmacology 40, 1–3 4. Moreno-De-Luca, A. et al. (2013) Developmental brain dysfunction: revival and expansion of old concepts based on new genetic evidence. Lancet Neurol. 12, 406–414 5. Gandal, M.J. et al. (2019) Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359, 693–697 6. Meyer, U. et al. (2011) Schizophrenia and autism: both shared and disorder-specific pathogenesis via perinatal inflammation? Pediatr. Res. 69, 26R–33R 7. Owen, M.J. and O’Donovan, M.C. (2017) Schizophrenia and the neurodevelopmental continuum: evidence from genomics. World Psychiatry 16, 227–235 8. Brown, A.S. and Meyer, U. (2018) Maternal immune activation and neuropsychiatric illness: a translational research perspective. Am. J. Psychiatry 175, 1073–1083 9. Gumusoglu, S.B. and Stevens, H.E. (2019) Maternal inflammation and neurodevelopmental programming: a review of preclinical outcomes and implications for translational psychiatry. Biol. Psychiatry 85, 107–121 10. Bilbo, S.D. et al. (2018) Beyond infection – maternal immune activation by environmental factors, microglial development, and relevance for autism spectrum disorders. Exp. Neurol. 299, 241–251 11. Chess, S. (1971) Autism in children with congenital rubella. J. Autism Child. Schizophr. 1, 33–47 12. Mednick, S.A. et al. (1988) Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch. Gen. Psychiatry 45, 189–192 13. Coyne, C.B. and Lazear, H.M. (2016) Zika virus – reigniting the TORCH. Nat. Rev. Microbiol. 14, 707–715 14. Meyer, U. (2013) Developmental neuroinflammation and schizophrenia. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 42, 20–34

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Outstanding Questions While factors promoting susceptibility or resilience to maternal immune activation (MIA) continue to be identified, the underlying cellular and molecular mechanisms remain elusive. What are the resilience pathways that lead to a partial or full protection against the sequelae of MIA and how exactly do susceptibility factors make the offspring vulnerable to this form of early-life adversity? Owing to the advances in singlecell biotechnology, the elucidation of cell-type-specific factors may offer valuable insights into the cellular mechanisms underlying the segregation of resilience and susceptibility in the context of MIA. Are there any maternal or fetal biomarkers that could distinguish susceptible from resilient offspring and predict their pathological outcomes in the context of MIA? Among susceptible offspring, the adverse effects induced by MIA may reflect early entry into a deviant neurodevelopmental route, but the specificity of subsequent disease or symptoms is likely to be influenced by the genetic and environmental context in which priming by MIA occurs. What are the mechanisms that shape the disease or symptom specificity in susceptible offspring of mothers exposed to immune activation during pregnancy? Can inherent resilience factors be intensified and/or can factors promoting resilience be applied exogenously to counteract susceptibility and promote protection against the negative health consequences of MIA? How can epidemiological research and genetic association studies be best integrated with basic research using models of MIA to advance our understanding of susceptibility and resilience in the context of MIA?

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