A correction has been applied to this article in:
Corrigendum: Virus-Induced Maternal Immune Activation as an Environmental Factor in the Etiology of Autism and Schizophrenia
Aïcha Massrali
Dwaipayan Adhya
Deepak P. Srivastava
Simon Baron-Cohen
Mark R. Kotter- 1Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
- 2Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
- 3Department of Basic and Clinical Neuroscience, King’s College London, London, United Kingdom
Maternal immune activation (MIA) is mediated by activation of inflammatory pathways resulting in increased levels of cytokines and chemokines that cross the placental and blood-brain barriers altering fetal neural development. Maternal viral infection is one of the most well-known causes for immune activation in pregnant women. MIA and immune abnormalities are key players in the etiology of developmental conditions such as autism, schizophrenia, ADHD, and depression. Experimental evidence implicating MIA in with different effects in the offspring is complex. For decades, scientists have relied on either MIA models or human epidemiological data or a combination of both. MIA models are generated using infection/pathogenic agents to induce an immunological reaction in rodents and monitor the effects. Human epidemiological studies investigate a link between maternal infection and/or high levels of cytokines in pregnant mothers and the likelihood of developing conditions. In this review, we discuss the importance of understanding the relationship between virus-mediated MIA and neurodevelopmental conditions, focusing on autism and schizophrenia. We further discuss the different methods of studying MIA and their limitations and focus on the different factors contributing to MIA heterogeneity.
Introduction
Maternal immune activation (MIA) is a major environmental factor known to increase likelihood of neurodevelopmental conditions such as autism (Paraschivescu et al., 2020) and schizophrenia (Kepinska et al., 2020; Purves-Tyson et al., 2021). MIA is mediated by activation of inflammatory pathways resulting in increased levels of cytokines and chemokines that cross the placental and blood-brain barriers (Patel et al., 2020; Mueller et al., 2021). This surge of inflammatory molecules alters neurodevelopment in the fetus (Patel et al., 2020; Purves-Tyson et al., 2021).
A number of maternal conditions may be responsible for triggering this inflammatory response, including autoimmune conditions (Chen et al., 2016), and asthma and allergic conditions (Gong et al., 2019). However, inflammatory responses caused by maternal viral infections remains one of the major environmental causes of MIA (Careaga et al., 2017; Baines et al., 2020; Cheslack-Postava and Brown, 2021). Case studies have associated viral infection from varicella, cytomegalovirus, mumps and herpes simplex virus with increased likelihood of autism (Patterson, 2011; Estes and McAllister, 2015). Understanding of the effects of virus-mediated MIA have also led researchers to consider the potential effects of maternal SARS-CoV-2 infection on fetal development (Reyes-Lagos et al., 2021).
Investigating the Effects of Maternal Immune Activation on Fetal Brain Development
Studying the effects of viral-induced MIA on the offspring can be very challenging. For decades, scientists relied on either MIA models or human epidemiological data or a combination of both.
Maternal Immune Activation Presentation From Human Epidemiological Studies
Epidemiological data has long implicated MIA as a likelihood factor for neurodevelopmental and neuropsychiatric conditions (Brown et al., 2004, 2014; Brown and Derkits, 2010; Estes and McAllister, 2016). More than 30 years ago an observation of higher incidence of schizophrenia and autism likelihood in winter/spring birth encouraged further investigations of specific infections such as influenza (Mednick et al., 1988; Kendell and Kemp, 1989). Earlier, human studies suggested associations between influenza and schizophrenia relying on ecological data, which focused on exposure to influenza epidemics in Europe, Australia and Japan (McGrath and Castle, 1995; Morgan et al., 1997; Izumoto et al., 1999; Mino et al., 2000). While some investigations reported an association between schizophrenia and infection during the second trimester of pregnancy (Mednick et al., 1988, 1994; Barr et al., 1990; Takei et al., 1996; Limosin et al., 2003), other studies reported conflicting results (Erlenmeyer-Kimling et al., 1994; Takei et al., 1995; Morgan et al., 1997; Westergaard et al., 1999). The initial study (Murray and Lewis, 1987) was met with a lot of criticism, as it failed to account for later onset schizophrenia and post adolescence changes (Folsom et al., 2006; Kochunov and Hong, 2014). Upon further investigations, studies suggest the “three-hit” model or “multiple hit” theory, making environmental, genetic, and maternal infections (e.g., influenza) potential hits (Keshavan, 1999; Davis et al., 2016). This theory also proposed that maternal infection increased the risk for childhood infections and later in life schizophrenia development (Blomström et al., 2016). Other studies looked at increased likelihood of schizophrenia with other types of infections such as measles (Fuller Torrey et al., 1988), mumps (O’Callaghan et al., 1994), and varicella zoster infections (Fuller Torrey et al., 1988; O’Callaghan et al., 1994), however, the results were conflicting and inconclusive. The inconsistency of the findings reported may in part be due to methodological limitation (Brown and Meyer, 2018). Ecological studies define exposure according to population-level prevalence at a specific location and a defined time and do not assess individuals in terms of actual infection evidence. More refined methods have emerged since then such as birth cohorts or case-control designs. Birth cohorts prospectively acquire serologic biomarkers of infection during individual pregnancies and investigate their association with higher likelihood of schizophrenia, autism and bipolar disorder (Meyer et al., 2009a; Brown and Derkits, 2010; Harvey and Boksa, 2012; Meyer, 2014; Estes and McAllister, 2016; Oliveira et al., 2017).
Studying MIA in humans relies on epidemiological data and does not investigate the potential biological pathways. The use of animal models filled this gap and provided the tool to examine the effects of MIA on fetal brain development.
Maternal Immune Activation Animal Models Reveal Underlying Neurodevelopmental Mechanisms
The first animal model to study the effects of viral infection-induced MIA on the offspring was developed by exposing a pregnant mouse to the human influenza virus (Fatemi et al., 2004). Studies have also used prenatal administration of immunogenic liposaccharides (LPS), a cell wall component of a gram-negative bacteria that induces an immunogenic reaction via the transmembrane protein toll-like receptor (TLR) 4, or polyriboinosinic–polyribocytidilic acid [Poly(I:C)] which is a synthetic analog of dsRNA and induces an immunogenic reaction in rodents via the TLR3 (Shi et al., 2003; Fatemi et al., 2004; Jurgens et al., 2012; Honda-Okubo et al., 2014; Xia et al., 2014). Administering these elements to pregnant rodents (Meyer et al., 2005; Saadani-Makki et al., 2008; Meyer, 2014) and to non-human primates (Bauman et al., 2013; Machado et al., 2015; Weir et al., 2015; Rose et al., 2017) triggers the maternal immune system, resulting in the secretion of pro-inflammatory cytokines, microglial activation, and the induction of pro-inflammatory transcription factors in the neonatal brain.
The effects of this activation on fetal brain development may vary according to multiple factors including the timing of infection and the resilience of the developing brain, increasing the likelihood of developing neurodevelopmental conditions later in life (Meyer, 2014). For instance, earlier studies reported that prenatal exposure to Poly(I:C) leads to brain histopathological features in the offspring similar to those reported in schizophrenia, such as decreased hippocampal, prefrontal, cortical and striatal volume, and enlarged ventricles (Zuckerman et al., 2003; Piontkewitz et al., 2011). Other studies reported that prenatal infections is associated with reduced Purkinje neurons in the cerebellum, commonly reported in autism cases (Shi et al., 2009; Naviaux et al., 2013).
In rodents, exposure to Poly(I:C) for a specific time course (48 h) is sufficient to produce an acute inflammatory response with elevated individual cytokine levels (Cunningham et al., 2007; Fortier et al., 2007).
Some studies showed that irreversible neurodevelopmental defects in rodents induced by Poly(I:C) are dependent on IL-6 and IL-17A induced by MIA (Choi et al., 2016; Smith et al., 2016; Wu et al., 2017). For instance, a single maternal injection of IL-6 on day 12.5 of mouse pregnancy causes pre-pulse inhibition (PPI) and latent inhibition (LI) deficits in the adult offspring, mimicking central features of schizophrenia (Smith et al., 2007). Moreover, even when introduced externally, IL-6 is sufficient to alter brain development in the offspring (Ponzio et al., 2007; Smith et al., 2007). IL-6 is known for its regulatory role in self-renewal among neuronal precursor cells, neuronal migration, and neurite outgrowth (Goines and Ashwood, 2013). IL-6 is also a key factor for T helper cells (TH17) differentiation in both human and mice. IL-17A, the main TH17 cytokine has been found elevated in the serum of some children with autism (Suzuki et al., 2011; Al-Ayadhi and Mostafa, 2012). Choi et al. (2016), investigated the effect of the pathological activation of maternal IL-17A pathways on fetal development by pre-treating pregnant mothers with IL-17A blocking antibodies before injecting them with poly(I:C) and examining cortical development in the fetus. They reported disorganized cortical phenotypes in offspring following in utero MIA and autism-like behavioral abnormalities in offspring (Choi et al., 2016).
Another cytokine that has been associated with autism-like behavioral changes in the mice offspring is IL-2 (Ponzio et al., 2007). Interestingly, the behavioral changes reported after the dual administration of LPS and Poly(I:C) were not seen when co-administering antibodies for IL-6 and IL-2, which demonstrates that the biological, structural, and behavioral changes are mediated by cytokines (Smith et al., 2007; Girard et al., 2010).
Collectively, these studies show that these pro-inflammatory cytokines (resulting from maternal infection) alter fetal brain development. The exact mechanism through which these cytokines affect the brain and increase the likelihood of neurodevelopmental conditions is not clear, however, one theory is that the maternal induced activation resulting from prenatal infections lead to alterations in immunogenic molecules known to regulate neuronal function in the offspring (Coiro et al., 2015; Estes and McAllister, 2015).
Limitations of MIA Models
Maternal immune activation models provide an invaluable experimental tool in investigating the link between maternal infection and inflammatory molecules and altered fetal brain development outcomes and likelihood of neuropsychiatric conditions (Meyer et al., 2009a,b; Harvey and Boksa, 2012; Meyer, 2014). Nevertheless, these models have certain limitations. First, the induction of a maternal immune response using non-virulent agents [such as LPS and Poly(I:C)] cannot reproduce the full spectrum of immune response that would normally result following an infectious pathogen. This method does not recapitulate pathogen-specific humoral and cellular immune reaction, which is crucial in understanding the specific mechanism contributing to the potential association (Shi et al., 2003; Meyer et al., 2005). Although it has been shown that the outcomes associated with MIA are not pathogen-specific but rather are mediated by immune molecules (e.g., cytokines) triggered by various infections, it is nonetheless important to note that the mechanisms mediating these responses are specific to the pathogen (Gilmore and Jarskog, 1997; Shi et al., 2003; Meyer et al., 2009b; Labouesse et al., 2015).
Additionally, the controlled nature of the environment in which the experiments are usually set up excludes the real-life influences in humans. These influences are important contributors to the susceptibility and resilience to maternal infection, influencing the outcomes (Meyers, 2019).
Lastly, the use of rodents as MIA animal models might sometimes be misleading and the field might benefit by expanding studies to include more species that are evolutionarily and ethologically closer to humans (Phillips et al., 2014; Bauman and Schumann, 2018).
Rhesus macaques can provide a model to replicate the findings found in rodents MIA models as they exhibit greater similarity to humans regarding gestational timelines and fetal brain development (Short et al., 2010; Phillips et al., 2014; Bauman and Schumann, 2018). For instance, Short et al. (2010) investigated the effects of immune activation during the third human trimester immune, which cannot be possible in rodents whose equivalent developmental stages occur postnatally. Moreover, Rhesus macaque MIA studies offer another benefit over rodents which is the ability to measure social behavioral phenotypes, such as social attention and detection of facial expressions (Machado et al., 2015). Other studies rely on induced pluripotent stem cells to advance our understanding of how specific cytokines induced by MIA can increase the likelihood of developing neurodevelopmental conditions (Warre-Cornish et al., 2020).
Heterogeneity in Maternal Immune Activation
Exposure to infections during pregnancy is quite common; almost 50% of pregnant women get respiratory tract infections while close to 20% getting urinary tract infections; nonetheless this high prevalence of maternal infection results in neurodevelopmental abnormalities in only a small portion of the exposed offspring (Milada et al., 2017; Weber-Stadlbauer, 2017; Brown and Meyer, 2018). This dichotomy might hold the key to certain protective that make certain pregnancies less susceptible to others, and mechanistically evidence has suggested impairment of cholinergic anti-inflammatory pathways in some pregnant mothers to be linked to a heightened inflammatory response (Reyes-Lagos et al., 2021).
Positive associations have been reported between maternal proinflammatory molecules [(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)] and increased likelihood of autism and schizophrenia. Other studies looked at the effects of increased levels of maternal cytokines on fetal brain development, and reported alterations in the connectivity of the amygdala (Graham et al., 2018; Rudolph et al., 2018), and frontolimbic white matter (Rasmussen et al., 2019) and observed cognitive abnormalities in toddlers (Graham et al., 2018; Rudolph et al., 2018; Rasmussen et al., 2019). These studies have confirmed the link between maternal infections, the role of abnormal levels of cytokines and the possibility of developmental anomalies in the offspring (Brown and Meyer, 2018; Gumusoglu and Stevens, 2019; Weber-Stadlbauer and Meyer, 2019). Notwithstanding the abundance of evidence implicating MIA in the etiology of neuropsychiatric conditions, this pathogenic model appears to be naïve. The type of infection, gestational time and the resilience of the maternal immune system are important factors to consider when trying to dissect the heterogeneity of the MIA-induced effects (Meyers, 2019).
Identifying the factors that promote resilience to the MIA or vulnerable factors that might make some pregnancies more susceptible is of crucial importance. Different maternal infections have distinct mode of actions even if the effect associated is dependent on the immune reaction and not the type of infection. Some pathogens can directly affect the offspring through vertical transmission from the mother to the fetus through the placenta or through breast milk. Other pathogens are non-transmissible from the mother to the fetus and they still impose serious influences on the offspring for neurodevelopmental and neuropsychiatric conditions (Mednick et al., 1988; Milada et al., 2017; Brown and Meyer, 2018). The specificity of the proinflammatory modulators produced post infection can influence the severity of MIA effects on fetal brain developments, is the specificity of the proinflammatory modulators produced post infection. For instance, recent studies using animal MIA models report that different subtypes of toll-like receptors produce different outcomes in the offspring (Meyer, 2014; Weber-Stadlbauer and Meyer, 2019). Prenatal activation of TLR3 resulted in cellular, neurochemical, and behavioral phenotypes of a hyperdopaminergic state (Luan et al., 2018) while prenatal activation of TLR4 induced a hypodopaminergic state (Kirsten et al., 2012). This supports the notion that different immunological molecules might have different pathological outcomes. The intensity and timing of infections are potential contributors to the susceptibility of certain pregnancies to MIA. Studies have shown a positive correlation between the severity of maternal inflammation and anomalies in the developing brain in the general population and in a schizophrenia cohort (Graham et al., 2018; Rudolph et al., 2018; Rasmussen et al., 2019). Similarly, dose-dependent effects have been confirmed in animal models of MIA (Meyer et al., 2005; Hornig et al., 2018).
Maternal exposure to TORCH pathogens imposes a higher probability of developing neurodevelopmental anomalies in the first half of the pregnancy while the effects of the infection are subtle and less severe in later gestational periods. Similarly, birth cohort studies suggested a trimester -dependent effects of MIA in increasing autism incidence (Hornig et al., 2018). Maternal micronutrients such as vitamin D, iron, zinc omega-3 fatty acids and choline and others have also been identified as important factors to promote resilience to infections and optimal immune functioning (Brown, 2011; Luan et al., 2018; Maggini et al., 2018; Mattei and Pietrobelli, 2019).
The microbiome has been recently added to the equation as a potential etiological factor not only in the neurodevelopmental condition but also in the dysregulation of immune functions (Conway and Brown, 2019). Therefore, it is one of the most crucial factors in MIA heterogeneity. Immune function abnormalities have been reported in autism and other neuropsychiatric conditions, and recent studies propose the involvement of the microbiota in this dysregulation (Hsiao et al., 2013; Cryan and Dinan, 2015; Erny et al., 2015). Experimental studies looking at the immunological effects of MIA reported dysregulation of offspring microbiota in adulthood (Hsiao et al., 2013; Mandal and Ghosh, 2013; Kim et al., 2017). A 2017 study found that mice that have more TH17 cells with segmented filamentous bacteria (SFB) were more susceptible to produce behavioral changes caused by MIA (Kim et al., 2017). Both MIA and microbiome dysregulation have been associated with alterations in fetal brain development, autism, and other neurodevelopmental conditions. Moreover, MIA activation alters maternal gut bacteria which can affect the microbiome of the offspring (Conway and Brown, 2019). This makes it extremely challenging to dissect the cause-effect relationship between MIA and the maternal microbiota, on offspring neurodevelopment.
Finally, the genetic background is a crucial contributor to the susceptibility or resilience to neurodevelopmental effect of MIA. Recent epidemiological studies have reported that familial history of psychiatric conditions posits synergistic interaction with MIA in increasing the probability of later developing schizophrenia. However, studies that examining common variants associated with schizophrenia showed no correlation interaction with MIA in increasing the likelihood of schizophrenia in the offspring. The latter does not remove the genetic background as a potential contributor to MIA heterogeneity but rather points out that polygenic scores are not proxy for genetic contribution (Clarke et al., 2009; Nielsen et al., 2013; Benros et al., 2016; Blomström et al., 2016). The genetic factors can be divided into factors that promote MIA susceptibility (Ayhan et al., 2016) or protection (Meyer et al., 2008). For instance, IL-10 polymorphisms have been associated with increased resilience against MIA effects as the increased production of IL-10 offer neurodevelopmental protection in the offspring post maternal infection (Meyer et al., 2008).
Potential Effects of SARS-COV-2 on Fetal Brain Development
SARS-CoV-2 infection is known to stimulate production of MIA-causing pro-inflammatory cytokines such as IL-6, IL10 and TNFα (Pedersen and Ho, 2020). Since the virus has only been identified recently (end of 2019) there are yet no studies that have been able to investigate neurodevelopmental consequences in the offspring of affected mothers. Based on its clinical manifestation and past “similar” infections, theories have been proposed that suggest potential effects on the offspring (Granja et al., 2021). Following infection with SARS-CoV-2, there is an uncontrolled release of inflammatory cytokines and chemokines that have been involved in brain development [e.g., interleukins (IL-1β,−2,−4,−6,−8,−10), tumor necrosis factor alpha, interferons (IFN-α, IFN-γ)] (Reyes-Lagos et al., 2021). Amid the exacerbated long-term inflammatory effects observed in COVID-19 patients and the lessons learned from of viral-mediated MIA effects on the progeny’s brain, it is crucial to consider the neurological consequences of maternal SARS-CoV-2 infection on the offspring.
Conclusion
Human epidemiological data and MIA animal models have consistently shown MIA is associated to increased likelihood of developmental neuropsychiatric conditions; however, the effects are very heterogenous. The high percentage of infected women that give birth to neurotypical offspring highlight that one pregnancy may be more susceptible to MIA adverse outcomes than the other. Studies to identify these factors aim to protect fragile pregnancies and inform us on potential contributors to the development of neurodevelopmental conditions.
Author Contributions
AM wrote the manuscript with support from DA and in consultation from DS, SB-C, and MK who supervised and provided critical feedback that shaped the final version of the manuscript.
Funding
SB-C received funding from the Wellcome Trust 214322/Z/18/Z. The results leading to this publication have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and AUTISM SPEAKS, Autistica, SFARI. SB-C also received funding from the Autism Center of Excellence, SFARI, the Templeton World Charitable Fund, the MRC, and the NIHR Cambridge Biomedical Research Center. The research was supported by the National Institute for Health Research (NIHR) Applied Research Collaboration East of England.
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Any views expressed are those of the author(s) and not necessarily those of the funder.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
Al-Ayadhi, L. Y., and Mostafa, G. A. (2012). Elevated serum levels of interleukin-17A in children with autism. J. .Neuroinflam. 9:158. doi: 10.1186/1742-2094-9-158
Ayhan, Y., McFarland, R., and Pletnikov, M. V. (2016). Animal models of gene-environment interaction in schizophrenia: A dimensional perspective. Prog. Neurobiol. 136, 1–27. doi: 10.1016/j.pneurobio.2015.10.002
Baines, K. J., Hillier, D. M., Haddad, F. L., Rajakumar, N., Schmid, S., and Renaud, S. J. (2020). Maternal Immune Activation Alters Fetal Brain Development and Enhances Proliferation of Neural Precursor Cells in Rats. Front. Immunol. 11:1145. doi: 10.3389/fimmu.2020.01145
Barr, C. E., Mednick, S. A., and Munk-Jorgensen, P. (1990). Exposure to Influenza Epidemics During Gestation and Adult Schizophrenia: A 40-Year Study. Arch. General Psych. 47, 869–874. doi: 10.1001/archpsyc.1990.01810210077012
Bauman, M. D., Iosif, A.-M., Ashwood, P., Braunschweig, D., Lee, A., Schumann, C. M., et al. (2013). Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Transl. Psych. 3:e278. doi: 10.1038/tp.2013.47
Bauman, M. D., and Schumann, C. M. (2018). Advances in nonhuman primate models of autism: Integrating neuroscience and behavior. Exp. Neurol. 299, 252–265. doi: 10.1016/j.expneurol.2017.07.021
Benros, M. E., Trabjerg, B. B., Meier, S., Mattheisen, M., Mortensen, P. B., Mors, O., et al. (2016). Influence of Polygenic Risk Scores on the Association Between Infections and Schizophrenia. Biol. Psych. 80, 609–616. doi: 10.1016/j.biopsych.2016.04.008
Blomström, Å, Karlsson, H., Gardner, R., Jörgensen, L., Magnusson, C., and Dalman, C. (2016). Associations between Maternal Infection during Pregnancy, Childhood Infections, and the Risk of Subsequent Psychotic Disorder - A Swedish Cohort Study of Nearly 2 Million Individuals. Schizoph. Bull. 42, 125–133. doi: 10.1093/schbul/sbv112
Brown, A. S. (2011). The environment and susceptibility to schizophrenia. Prog. Neurobiol. 93, 23–58. doi: 10.1016/j.pneurobio.2010.09.003
Brown, A. S., Begg, M. D., Gravenstein, S., Schaefer, C. A., Wyatt, R. J., Bresnahan, M., et al. (2004). Serologic evidence of prenatal influenza in the etiology of schizophrenia. Arch. General Psych. 61, 774–780. doi: 10.1001/archpsyc.61.8.774
Brown, A. S., and Derkits, E. J. (2010). Prenatal Infection and Schizophrenia: A Review of Epidemiologic and Translational Studies. Am. J. Psych. 167, 261–280. doi: 10.1176/appi.ajp.2009.09030361
Brown, A. S., and Meyer, U. (2018). Maternal Immune Activation and Neuropsychiatric Illness: A Translational Research Perspective. Am. J. Psych. 175, 1073–1083. doi: 10.1176/appi.ajp.2018.17121311
Brown, A. S., Sourander, A., Hinkka-Yli-Salomäki, S., McKeague, I. W., Sundvall, J., and Surcel, H. M. (2014). Elevated maternal C-reactive protein and autism in a national birth cohort. Mol. Psych. 19, 259–264. doi: 10.1038/mp.2012.197
Careaga, M., Murai, T., and Bauman, M. D. (2017). Maternal Immune Activation and Autism Spectrum Disorder: From Rodents to Nonhuman and Human Primates. Biol. Psych. 81, 391–401. doi: 10.1016/j.biopsych.2016.10.020
Chen, S. W., Zhong, X. S., Jiang, L. N., Zheng, X. Y., Xiong, Y. Q., Ma, S. J., et al. (2016). Maternal autoimmune diseases and the risk of autism spectrum disorders in offspring: A systematic review and meta-analysis. Behav. Brain Res. 296, 61–69. doi: 10.1016/j.bbr.2015.08.035
Cheslack-Postava, K., and Brown, A. S. (2021). Prenatal infection and schizophrenia: A decade of further progress. Schizoph. Res. [Epub Online ahead of print]. doi: 10.1016/j.schres.2021.05.014
Choi, G. B., Yim, Y. S., Wong, H., Kim, S., Kim, H., Kim, S. V., et al. (2016). The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939. doi: 10.1126/science.aad0314
Clarke, M. C., Tanskanen, A., Huttunen, M., Whittaker, J. C., and Cannon, M. (2009). Evidence for an interaction between familial liability and prenatal exposure to infection in the causation of schizophrenia. Am. J. Psych. 166, 1025–1030. doi: 10.1176/appi.ajp.2009.08010031
Coiro, P., Padmashri, R., Suresh, A., Spartz, E., Pendyala, G., Chou, S., et al. (2015). Impaired synaptic development in a maternal immune activation mouse model of neurodevelopmental disorders. Brain Behav. Immunity 50, 249–258. doi: 10.1016/j.bbi.2015.07.022
Conway, F., and Brown, A. S. (2019). Maternal Immune Activation and Related Factors in the Risk of Offspring Psychiatric Disorders. Front. Psych. 10:430. doi: 10.3389/fpsyt.2019.00430
Cryan, J. F., and Dinan, T. G. (2015). Gut microbiota: Microbiota and neuroimmune signalling-Metchnikoff to microglia. Nat. Rev. Gastroenterol. Hepatol. 12, 494–496. doi: 10.1038/nrgastro.2015.127
Cunningham, C., Campion, S., Teeling, J., Felton, L., and Perry, V. H. (2007). The sickness behaviour and CNS inflammatory mediator profile induced by systemic challenge of mice with synthetic double-stranded RNA (poly I:C). Brain Behav. Immun. 21, 490–502. doi: 10.1016/j.bbi.2006.12.007
Davis, J., Eyre, H., Jacka, F., Dodd, S., Dean, O., McEwen, S., et al. (2016). A review of vulnerability and risks for schizophrenia: Beyond the two hit hypothesis. Neurosci. Biobehav. Rev. 65, 185–194. doi: 10.1016/j.neubiorev.2016.03.017
Erlenmeyer-Kimling, L., Folnegović, Z., Hrabak-Žerjavić, V., Borčić, B., Folnegović-Šmalc, V., and Susser, E. (1994). Schizophrenia and prenatal exposure to the 1957 A2 influenza epidemic in Croatia. Am. J. Psych. 151, 1496–1498. doi: 10.1176/ajp.151.10.1496
Erny, D., Hrabe, de Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., et al. (2015). Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977. doi: 10.1038/nn.4030
Estes, M. L., and McAllister, A. K. (2015). Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat. Rev. Neurosci. 16, 469–486. doi: 10.1038/nrn3978
Estes, M. L., and McAllister, A. K. (2016). Maternal immune activation: Implications for neuropsychiatric disorders. Science 353, 772–777. doi: 10.1126/science.aag3194
Fatemi, S. H., Araghi-Niknam, M., Laurence, J. A., Stary, J. M., Sidwell, R. W., and Lee, S. (2004). Glial fibrillary acidic protein and glutamic acid decarboxylase 65 and 67 kDa proteins are increased in brains of neonatal BALB/c mice following viral infection in utero. Schizoph. Res. 69, 121–123. doi: 10.1016/S0920-9964(03)00175-0
Folsom, D., Lebowitz, B., Lindamer, L., Palmer, B., Patterson, T., and Jeste, D. (2006). Schizophrenia in late life: emerging issues. Dialog. Clin. Neurosci. 8, 45–52. doi: 10.31887/DCNS.2006.8.1/dfolsom
Fortier, M. E., Luheshi, G. N., and Boksa, P. (2007). Effects of prenatal infection on prepulse inhibition in the rat depend on the nature of the infectious agent and the stage of pregnancy. Behav. Brain Res. 181, 270–277. doi: 10.1016/j.bbr.2007.04.016
Fuller Torrey, E., Rawlings, R., and Waldman, I. N. (1988). Schizophrenic births and viral diseases in two states. Nat. Rev. Neurosci. 1, 73–77. doi: 10.1016/0920-9964(88)90043-6
Gilmore, J. H., and Jarskog, L. F. (1997). Exposure to infection and brain development: cytokines in the pathogenesis of schizophrenia. Nat. Rev. Neurosci. 24, 365–367. doi: 10.1016/s0920-9964(96)00123-5
Girard, S., Tremblay, L., Lepage, M., and Sébire, G. (2010). IL-1 Receptor Antagonist Protects against Placental and Neurodevelopmental Defects Induced by Maternal Inflammation. J. Immunol. 184, 3997–4005. doi: 10.4049/jimmunol.0903349
Goines, P. E., and Ashwood, P. (2013). Cytokine dysregulation in autism spectrum disorders (ASD): Possible role of the environment. Neurotoxicol. Teratol. 36, 67–81. doi: 10.1016/j.ntt.2012.07.006
Gong, T., Lundholm, C., Rejno, G., Bolte, S., Larsson, H., D’Onofrio, B. M., et al. (2019). Parental asthma and risk of autism spectrum disorder in offspring: A population and family-based case-control study. Clin. Exp. Allergy 49, 883–891. doi: 10.1111/cea.13353
Graham, A. M., Rasmussen, J. M., Rudolph, M. D., Heim, C. M., Gilmore, J. H., Styner, M., et al. (2018). Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age. Biol. Psych. 83, 109–119. doi: 10.1016/j.biopsych.2017.05.027
Granja, M. G., Oliveira, A. C. D. R., De Figueiredo, C. S., Gomes, A. P., Ferreira, E. C., Giestal-De-Araujo, E., et al. (2021). SARS-CoV-2 Infection in Pregnant Women: Neuroimmune-Endocrine Changes at the Maternal-Fetal Interface. Neuro Immuno Modulat. 28, 1–21. doi: 10.1159/000515556
Gumusoglu, S. B., and Stevens, H. E. (2019). Maternal Inflammation and Neurodevelopmental Programming: A Review of Preclinical Outcomes and Implications for Translational Psychiatry. Biol. Psych. 85, 107–121. doi: 10.1016/j.biopsych.2018.08.008
Harvey, L., and Boksa, P. (2012). Prenatal and postnatal animal models of immune activation: relevance to a range of neurodevelopmental disorders. Devel. Neurobiol. 72, 1335–1348. doi: 10.1002/dneu.22043
Honda-Okubo, Y., Kolpe, A., Li, L., and Petrovsky, N. (2014). A single immunization with inactivated H1N1 influenza vaccine formulated with delta inulin adjuvant (Advax™) overcomes pregnancy-associated immune suppression and enhances passive neonatal protection. Vaccine 32, 4651–4659. doi: 10.1016/j.vaccine.2014.06.057
Hornig, M., Bresnahan, M. A., Che, X., Schultz, A. F., Ukaigwe, J. E., Eddy, M. L., et al. (2018). Prenatal fever and autism risk. Mol. Psych. 23, 759–766. doi: 10.1038/mp.2017.119
Hsiao, E. Y., McBride, S. W., Hsien, S., Sharon, G., Hyde, E. R., McCue, T., et al. (2013). Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463. doi: 10.1016/j.cell.2013.11.024
Izumoto, Y., Inoue, S., and Yasuda, N. (1999). Schizophrenia and the influenza epidemics of 1957 in Japan. Biol. Psych. 46, 119–124.
Jurgens, H. A., Amancherla, K., and Johnson, R. W. (2012). Influenza Infection Induces Neuroinflammation, Alters Hippocampal Neuron Morphology, and Impairs Cognition in Adult Mice. J. Neurosci. 32, 3958–3968. doi: 10.1523/JNEUROSCI.6389-11.2012
Kendell, R. E., and Kemp, I. W. (1989). Maternal Influenza in the Etiology of Schizophrenia. Archiv. General Psych. 46, 878–882. doi: 10.1001/archpsyc.1989.01810100020004
Kepinska, A. P., Iyegbe, C. O., Vernon, A. C., Yolken, R., Murray, R. M., and Pollak, T. A. (2020). Schizophrenia and Influenza at the Centenary of the 1918-1919 Spanish Influenza Pandemic: Mechanisms of Psychosis Risk. Front. Psych. 11:72. doi: 10.3389/fpsyt.2020.00072
Keshavan, M. (1999). Development, disease and degeneration in schizophrenia: a unitary pathophysiological model. J. Psych. Res. 33, 513–521. doi: 10.1016/s0022-3956(99)00033-3
Kim, S., Kim, H., Yim, Y. S., Ha, S., Atarashi, K., Tan, T. G., et al. (2017). Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549, 528–532. doi: 10.1038/nature23910
Kirsten, T. B., Chaves-Kirsten, G. P., Chaible, L. M., Silva, A. C., Martins, D. O., Britto, L. R., et al. (2012). Hypoactivity of the central dopaminergic system and autistic-like behavior induced by a single early prenatal exposure to lipopolysaccharide. J. Neurosci. Res. 90, 1903–1912. doi: 10.1002/jnr.23089
Kochunov, P., and Hong, L. E. (2014). Neurodevelopmental and neurodegenerative models of schizophrenia: white matter at the center stage. Schizophr. Bull. 40, 721–728. doi: 10.1093/schbul/sbu070
Labouesse, M. A., Langhans, W., and Meyer, U. (2015). Long-term pathological consequences of prenatal infection: beyond brain disorders. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309, R1–R12. doi: 10.1152/ajpregu.00087.2015
Limosin, F., Rouillon, F., Payan, C., Cohen, J. M., and Strub, N. (2003). Prenatal exposure to influenza as a risk factor for adult schizophrenia. Acta Psych. Scand. 107, 331–335. doi: 10.1034/j.1600-0447.2003.00052.x
Luan, W., Hammond, L. A., Vuillermot, S., Meyer, U., and Eyles, D. W. (2018). Maternal Vitamin D Prevents Abnormal Dopaminergic Development and Function in a Mouse Model of Prenatal Immune Activation. Sci. Rep. 8:9741. doi: 10.1038/s41598-018-28090-w
Machado, C. J., Whitaker, A. M., Smith, S. E. P., Patterson, P. H., and Bauman, M. D. (2015). Maternal immune activation in nonhuman primates alters social attention in juvenile offspring. Biol. Psych. 77, 823–832. doi: 10.1016/j.biopsych.2014.07.035
Maggini, S., Pierre, A., and Calder, P. C. (2018). Immune Function and Micronutrient Requirements Change over the Life Course. Nutrients 10:1531. doi: 10.3390/nu10101531
Mandal, S., and Ghosh, K. (2013). Isolation of tannase-producing microbiota from the gastrointestinal tracts of some freshwater fish. J. Appl. Ichthyol. 29, 145–153.
Mattei, D., and Pietrobelli, A. (2019). Micronutrients and Brain Development. Curr. Nutr. Rep. 8, 99–107.
McGrath, J., and Castle, D. (1995). Does Influenza Cause Schizophrenia? A Five Year Review. Austral. N. Zeal. J. Psych. 29, 23–31.
Mednick, S., Huttunen, M. O., and Machón, R. A. (1994). Prenatal Influenza Infections and Adult Schizophrenia. Schizoph. Bull. 20, 263–267. doi: 10.1093/schbul/20.2.263
Mednick, S. A., Machon, R. A., Huttunen, M. O., and Bonett, D. (1988). Adult Schizophrenia Following Prenatal Exposure to an Influenza Epidemic. Archiv. General Psych. 45, 189–192.
Meyer, U. (2014). Prenatal Poly(I:C) Exposure and Other Developmental Immune Activation Models in Rodent Systems. Biol. Psych. 75, 307–315. doi: 10.1016/j.biopsych.2013.07.011
Meyer, U., Feldon, J., and Fatemi, S. H. (2009a). In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neurosci. Biobehav. Rev. 33, 1061–1079. doi: 10.1016/j.neubiorev.2009.05.001
Meyer, U., Feldon, J., Schedlowski, M., and Yee, B. K. (2005). Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia. Neurosci. Biobehav. Rev. 29, 913–947. doi: 10.1016/j.neubiorev.2004.10.012
Meyer, U., Feldon, J., and Yee, B. K. (2009b). A review of the fetal brain cytokine imbalance hypothesis of schizophrenia. Schizoph. Bull. 35, 959–972. doi: 10.1093/schbul/sbn022
Meyer, U., Murray, P. J., Urwyler, A., Yee, B. K., Schedlowski, M., and Feldon, J. (2008). Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling. Mol. Psych. 13, 208–221. doi: 10.1038/sj.mp.4002042
Meyers, U. (2019). Neurodevelopmental Resilience and Susceptibility to Maternal Immune Activation. Trends Neurosci. 42, 793–806. doi: 10.1016/j.tins.2019.08.001
Milada, M., Xiaoyu, C., Ezra, S., Bruce, L., Ted, R.-K., Per, M., et al. (2017). Epidemiological and Serological Investigation into the Role of Gestational Maternal Influenza Virus Infection and Autism Spectrum Disorders. mSphere 2, e159–e117. doi: 10.1128/mSphere.00159-17
Mino, Y., Oshima, I., Tsuda, T., and Okagami, K. (2000). No relationship between schizophrenic birth and influenza epidemics in Japan. J. Psych. Res. 34, 133–138. doi: 10.1016/s0022-3956(00)00003-0
Morgan, V., Castle, D., Page, A., Fazio, S., Gurrin, L., Burton, P., et al. (1997). Influenza epidemics and incidence of schizophrenia, affective disorders and mental retardation in Western Australia: no evidence of a major effect. Schizoph. Res. 26, 25–39. doi: 10.1016/S0920-9964(97)00033-9
Mueller, F. S., Scarborough, J., Schalbetter, S. M., Richetto, J., Kim, E., Couch, A., et al. (2021). Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation. Mol. Psych. 26, 396–410. doi: 10.1038/s41380-020-00952-8
Murray, R., and Lewis, S. (1987). Is schizophrenia a neurodevelopmental disorder? Br. Med. J. 10:295.
Naviaux, R. K., Zolkipli, Z., Wang, L., Nakayama, T., Naviaux, J. C., Le, T. P., et al. (2013). Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model. PLoS One. 8:e57380. doi: 10.1371/journal.pone.0057380
Nielsen, P. R., Laursen, T. M., and Mortensen, P. B. (2013). Association between parental hospital-treated infection and the risk of schizophrenia in adolescence and early adulthood. Schizophr. Bull. 39, 230–237. doi: 10.1093/schbul/sbr149
O’Callaghan, E., Sham, P. C., Takei, N., Murray, G., Glover, G., Hare, E. H., et al. (1994). The Relationship of Schizophrenic Births to 16 Infectious Diseases. Br. J. Psych. 165, 353–356. doi: 10.1192/bjp.165.3.353
Oliveira, J., Oliveira-Maia, A. J., Tamouza, R., Brown, A. S., and Leboyer, M. (2017). Infectious and immunogenetic factors in bipolar disorder. Acta Psychiatr. Scand. 136, 409–423. doi: 10.1111/acps.12791
Paraschivescu, C., Barbosa, S., Lorivel, T., Glaichenhaus, N., and Davidovic, L. (2020). Cytokine changes associated with the maternal immune activation (MIA) model of autism: A penalized regression approach. PLoS One. 15:e0231609. doi: 10.1371/journal.pone.0231609
Patel, S., Dale, R. C., Rose, D., Heath, B., Nordahl, C. W., Rogers, S., et al. (2020). Maternal immune conditions are increased in males with autism spectrum disorders and are associated with behavioural and emotional but not cognitive co-morbidity. Transl. Psych. 10:286. doi: 10.1038/s41398-020-00976-2
Patterson, P. H. (2011). Maternal infection and immune involvement in autism. Trends Mol. Med. 17, 389–394. doi: 10.1016/j.molmed.2011.03.001
Pedersen, S. F., and Ho, Y. C. (2020). SARS-CoV-2: a storm is raging. J. Clin. Invest. 130, 2202–2205. doi: 10.1172/JCI137647
Phillips, K. A., Bales, K. L., Capitanio, J. P., Conley, A., Czoty, P. W., ’t Hart, B. A., et al. (2014). Why primate models matter. Am. J. Primatol. 76, 801–827. doi: 10.1002/ajp.22281
Piontkewitz, Y., Arad, M., and Weiner, I. (2011). Abnormal Trajectories of Neurodevelopment and Behavior Following In Utero Insult in the Rat. Biol. Psych. 70, 842–851. doi: 10.1016/j.biopsych.2011.06.007
Ponzio, N., Servatius, R., Beck, K., Marzouk, A., and Kreider, I. T. (2007). Cytokine Levels during Pregnancy Influence Immunological Profiles and Neurobehavioral Patterns of the Offspring. Anna. N. Y. Acad. Sci. 1107, 118–128. doi: 10.1196/annals.1381.013
Purves-Tyson, T. D., Weber-Stadlbauer, U., Richetto, J., Rothmond, D. A., Labouesse, M. A., Polesel, M., et al. (2021). Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation. Mol. Psych. 26, 849–863. doi: 10.1038/s41380-019-0434-0
Rasmussen, J. M., Graham, A. M., Entringer, S., Gilmore, J. H., Styner, M., Fair, D. A., et al. (2019). Maternal Interleukin-6 concentration during pregnancy is associated with variation in frontolimbic white matter and cognitive development in early life. NeuroImage 185, 825–835. doi: 10.1016/j.neuroimage.2018.04.020
Reyes-Lagos, J. J., Abarca-Castro, E. A., Echeverria, J. C., Mendieta-Zeron, H., Vargas-Caraveo, A., and Pacheco-Lopez, G. (2021). A Translational Perspective of Maternal Immune Activation by SARS-CoV-2 on the Potential Prenatal Origin of Neurodevelopmental Disorders: The Role of the Cholinergic Anti-inflammatory Pathway. Front. Psychol. 12:614451. doi: 10.3389/fpsyg.2021.614451
Rose, D. R., Careaga, M., Van de Water, J., McAllister, K., Bauman, M. D., and Ashwood, P. (2017). Long-term altered immune responses following fetal priming in a non-human primate model of maternal immune activation. Brain Behav. Immun. 63, 60–70. doi: 10.1016/j.bbi.2016.11.020
Rudolph, M. D., Graham, A. M., Feczko, E., Miranda-Dominguez, O., Rasmussen, J. M., Nardos, R., et al. (2018). Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring. Nat. Neurosci. 21, 765–772. doi: 10.1038/s41593-018-0128-y
Saadani-Makki, F., Kannan, S., Lu, X., Janisse, J., Dawe, E., Edwin, S., et al. (2008). Intrauterine administration of endotoxin leads to motor deficits in a rabbit model: a link between prenatal infection and cerebral palsy. Am. J. Obstetr. Gynecol. 199, 651.e1–651.e7. doi: 10.1016/j.ajog.2008.06.090
Shi, L., Fatemi, S. H., Sidwell, R. W., and Patterson, P. H. (2003). Maternal Influenza Infection Causes Marked Behavioral and Pharmacological Changes in the Offspring. J. Neurosci. 23, 297–302. doi: 10.1523/JNEUROSCI.23-01-00297.2003
Shi, L., Smith, S. E. P., Malkova, N., Tse, D., Su, Y., and Patterson, P. H. (2009). Activation of the maternal immune system alters cerebellar development in the offspring. Brain Behav. Immun. 23, 116–123. doi: 10.1016/j.bbi.2008.07.012
Short, S. J., Lubach, G. R., Karasin, A. I., Olsen, C. W., Styner, M., Knickmeyer, R. C., et al. (2010). Maternal influenza infection during pregnancy impacts postnatal brain development in the rhesus monkey. Biol. Psych. 67, 965–973. doi: 10.1016/j.biopsych.2009.11.026
Smith, D. K., Yang, J., Liu M-l, and Zhang C-l. (2016). Small Molecules Modulate Chromatin Accessibility to Promote NEUROG2-Mediated Fibroblast-to-Neuron Reprogramming. Stem Cell Reports 7, 955–969. doi: 10.1016/j.stemcr.2016.09.013
Smith, S. E. P., Li, J., Garbett, K., Mirnics, K., and Patterson, P. H. (2007). Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6. J. Neurosci. 27, 10695–10702. doi: 10.1523/JNEUROSCI.2178-07.2007
Suzuki, K., Matsuzaki, H., Iwata, K., Kameno, Y., Shimmura, C., Kawai, S., et al. (2011). Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS One. 6:e20470. doi: 10.1371/journal.pone.0020470
Takei, N., Mortensen, P. B., Klæning, U., Murray, R. M., Sham, P. C., O’Callaghan, E., et al. (1996). Relationship between in utero exposure to influenza epidemics and risk of schizophrenia in Denmark. Biol. Psych. 40, 817–824. doi: 10.1016/0006-3223(95)00592-7
Takei, N., Van Os, J., and Murray, R. M. (1995). Maternal exposure to influenza and risk of schizophrenia: A 22 year study from The Netherlands. J. Psychiatr. Res. 29, 435–445. doi: 10.1016/0022-3956(95)00031-3
Warre-Cornish, K., Perfect, L., Nagy, R., Duarte, R. R., Reid, M. J., Raval, P., et al. (2020). Interferon-γ signaling in human iPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes. Devel. Neurosci. 6:eaay9506. doi: 10.1126/sciadv.aay9506
Weber-Stadlbauer, U. (2017). Epigenetic and transgenerational mechanisms in infection-mediated neurodevelopmental disorders. Transl. Psych. 7:e1113. doi: 10.1038/tp.2017.78
Weber-Stadlbauer, U., and Meyer, U. (2019). Challenges and opportunities of a-priori and a-posteriori variability in maternal immune activation models. Curr. Opin. Behav. Sci. 28, 119–128.
Weir, R. K., Forghany, R., Smith, S. E., Patterson, P. H., McAllister, A. K., Schumann, C. M., et al. (2015). Preliminary evidence of neuropathology in nonhuman primates prenatally exposed to maternal immune activation. Brain Behav. Immun. 48, 139–146. doi: 10.1016/j.bbi.2015.03.009
Westergaard, T., Mortensen, P. B., Pedersen, C. B., Wohlfahrt, J., and Melbye, M. (1999). Exposure to Prenatal and Childhood Infections and the Risk of Schizophrenia: Suggestions From a Study of Sibship Characteristics and Influenza Prevalence. Archiv. General Psych. 56, 993–998. doi: 10.1001/archpsyc.56.11.993
Wu, W. L., Hsiao, E. Y., Yan, Z., Mazmanian, S. K., and Patterson, P. H. (2017). The placental interleukin-6 signaling controls fetal brain development and behavior. Brain Behav. Immun. 62, 11–23. doi: 10.1016/j.bbi.2016.11.007
Xia, Y., Qi, F., Zou, J., and Yao, Z. (2014). Influenza A(H1N1) vaccination during early pregnancy transiently promotes hippocampal neurogenesis and working memory. Involvement of Th1/Th2 balance. Brain Res. 1592, 34–43. doi: 10.1016/j.brainres.2014.09.076
Zuckerman, L., Rehavi, M., Nachman, R., and Weiner, I. (2003). Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: A novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology 28, 1778–1789. doi: 10.1038/sj.npp.1300248
Keywords: autism spectrum conditions, autism, maternal immune activation (MIA), SARS-CoV-2, schizophrenia, LPS, Poly(I:C)
Citation: Massrali A, Adhya D, Srivastava DP, Baron-Cohen S and Kotter MR (2022) Virus-Induced Maternal Immune Activation as an Environmental Factor in the Etiology of Autism and Schizophrenia. Front. Neurosci. 16:834058. doi: 10.3389/fnins.2022.834058
Received: 12 December 2021; Accepted: 01 March 2022;
Published: 12 April 2022.
Edited by:
Yasir Ahmed Syed, Cardiff University, United KingdomReviewed by:
Brian Kalish, University of Toronto, CanadaStefano Sotgiu, University of Sassari, Italy
Copyright © 2022 Massrali, Adhya, Srivastava, Baron-Cohen and Kotter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Aïcha Massrali, a.massrali@gmail.com