The Origins of Schizophrenia

Birth in winter or spring months is an accepted risk factor for schizophrenia, and it is possible that the prevalence of influenza in winter months is responsible (Tochigi et al., 2004). Over 25 studies have analyzed the prevalence of schizophrenia among subjects in utero during influenza epidemics, and most have found an increased occurrence among exposed offspring. More recently, Brown and colleagues (Brown et al., 2002; Brown et al., 2004; Brown, 2006) used a prospective approach to assay prenatal serum specimens for influenza antibody in offspring drawn from a cohort of over 12,000 pregnant women, and found that influenza infection during the first trimester is associated with a sevenfold increase in the risk for schizophrenia in the offspring (Brown et al., 2004). For early to mid-gestation, a threefold effect was demonstrated. Because of the high prevalence of influenza infection, the authors estimated that 14–21% of schizophrenia cases would not have occurred if maternal influenza had been prevented. These findings are further supported by an association between elevated cytokines in maternal serum and schizophrenia in the offspring (Brown & Derkits, 2010). In addition, there is evidence from serologic data and obstetrics records linking maternal rubella, toxoplasma, and genital-reproductive and bacterial infections with risk for schizophrenia (reviewed by Sorensen et al., 2009; Brown & Derkits, 2010). What is most striking is that maternal rubella infection increases the risk ten- to twentyfold. Because several of these infections are nonoverlapping, an attributable risk calculation summing the influenza, toxoplasma, and genital-reproductive infection risk factors suggests that as many as 33% of schizophrenia cases would not occur if all of these maternal infections could be prevented (chapter 1, this book; Brown & Derkits, 2010).

These links are even more remarkable considering that these epidemiologic studies did not screen for susceptibility genotype. Because of the strong genetic component in schizophrenia, it is possible that maternal infection is a risk factor only in genetically susceptible individuals. Thus, the risk associated with maternal infection for individuals with the appropriate genotype may be considerably greater than those figures just cited here.

The link between maternal infection and mental illness is reinforced by findings of immune dysregulation in schizophrenia. There are many reports of abnormalities in peripheral immune cells, as well as associations between schizophrenia and autoimmunity and variants of genes for cytokines, their receptors, and the major histocompatibility complex (reviewed by Sperner-Unterweger, 2005; Muller & Schwarz, 2006; Strous & Shoenfeld, 2006; Knight et al., 2007; Potvin et al., 2008; Shi et al., 2009a; Stefansson et al., 2009). There is also evidence of abnormal expression of immune-related genes in the brains of patients with schizophrenia (Arion et al., 2007; Saetre et al., 2007). This does not appear to be classical inflammation, but rather a dysregulation. The relevance of this growing literature is, first, that the immune status of the mother and fetus is likely to be of central importance for their responses to maternal infection. Second, the diverse nature of the various types of maternal infections that increase risk for schizophrenia in the offspring indicates that the critical response mechanism is activation of the maternal immune response. This conclusion is supported by studies of animal models of maternal infection.

Questions have been raised as to whether it is possible to develop animal models that are relevant for schizophrenia, a disorder that has been termed “uniquely human.” However, the goal here is not necessarily to develop an animal model of schizophrenia, but rather to determine which features of schizophrenia may be expressed in an animal model of maternal infection. Indeed, many such features can be examined in animals, including behaviors and neuropathology. Some of the behavioral tests that are relevant for schizophrenia include those for anxiety, social interaction, sensorimotor gating (prepulse inhibition, or PPI), latent inhibition, working memory, and responses to antipsychotic and psychomimetic drugs. Some of the neuropathologies that are relevant for schizophrenia include enlarged ventricles; altered dopamine neurotransmission; various changes in GABA (gamma-aminobutyric acid) neurotransmission in parvalbumin-expressing chandelier neurons in the prefrontal cortex; atrophy in the hippocampus, cerebellum, and thalamus; altered myelination; and dysregulation of immune-related molecules in the brain and periphery (Dean et al., 2009). Animal models of maternal infection that exhibit many of these features are being effectively used to explore how activation of the maternal immune system leads to changes in fetal brain development. Moreover, potential approaches to prevention and treatment of symptoms are being tested in these models. Thus, these models have both face (they reproduce features of the disease) and construct (based on environmental or genetic risk factors for the disease) validity, as well as potential therapeutic value for schizophrenia.

Given the high frequency of influenza infection in human populations, and strong evidence linking maternal influenza infection with schizophrenia, it is logical to investigate this form of respiratory infection in animals. Moreover, mice are a logical choice because of their utility in genetic studies. Exposure of pregnant C57BL/6 or BALB/C mice to a strain of human influenza virus adapted to mice results in offspring with several histologic abnormalities in the hippocampus and cortex (Fatemi et al., 1999; Fatemi et al., 2000). These include modest layer- and region-specific changes in the expression of the presynaptic marker SNAP-25, as well as in nNOS and reelin. These offspring also display a spatially restricted deficit in Purkinje cells (Shi et al., 2009b), which is commonly found in autism and also occurs in schizophrenia (Ho, Mola, & Andreasen, 2004), as well as smaller and more densely packed pyramidal cells, a finding also reminiscent of schizophrenia pathology (Fatemi et al., 2002). Changes in white matter are also reported in the cerebellum, although these alterations are inconsistent across the postnatal ages examined (Fatemi et al., 2009). In addition, neonatal mice born to infected mothers display a striking abnormality in neuronal migration to layer 2/3 in the embryonic cortex (Shi et al., 2006). This migration defect is particularly interesting because it closely resembles that observed when DISC1 (Disrupted-in-Schizophrenia 1, a leading candidate gene for schizophrenia) is experimentally down-regulated in the mouse fetus (Kamiya et al., 2005). Immunostaining for glial fibrillary acidic protein (GFAP) reveals a striking elevation in neonatal offspring, suggesting at least a transient inflammatory state in the brain (Fatemi et al., 2004). This is potentially relevant for the signs of chronic immune dysregulation observed in schizophrenia already cited here, as well as in other animal models discussed later in this chapter. There are also several reports of changes in gene expression in the neocortex and cerebellum in postnatal offspring of infected mothers (Fatemi et al., 2008), and some of these changes have also been observed in adult subjects with schizophrenia.

Behavioral analyses demonstrate that adult mice born to infected mothers display abnormalities that are relevant to schizophrenia, including deficits in social interaction, PPI of the acoustic startle, and increased anxiety (Shi et al., 2003). It is important that the PPI deficit is ameliorated by acute administration of antipsychotic drugs (clozapine and chlorpromazine) and exacerbated by a psychomimetic drug (ketamine).

Given that influenza infection normally is restricted to the respiratory tract, it was surprising that the virus was reported to be present in the fetus following maternal infection in mice (Aronsson et al., 2002). A subsequent report was, however, unable to confirm the presence of virus in the fetus or in the newborn brain following maternal infection (Shi, Tu, & Patterson, 2005). This suggested that it is the maternal immune response that drives pathology in the fetal brain. This hypothesis receives strong support from the finding that MIA using the synthetic, double stranded RNA, poly(I:C), which acts through the toll-like receptor 3 (TLR3), is sufficient to cause all of the behavioral and histologic abnormalities seen thus far in the offspring of maternal influenza-infected mothers (Shi et al., 2003; Smith et al., 2007; Shi et al., 2009b). The poly(I:C) model of MIA has been adopted widely, and many results have been reproduced among the laboratories, including deficits in PPI, social interaction, working memory, anxiety, and latent inhibition, increased amphetamine- and MK-801-induced locomotion and altered reversal learning (Shi et al., 2003; Zuckerman et al., 2003; Zuckerman & Weiner, 2005; Meyer et al., 2006b; Ozawa et al., 2006; Meyer, Yee, & Feldon, 2007; Smith et al., 2007; Wolff & Bilkey, 2008), all of which are consistent with the schizophrenia phenotype. Reminiscent of the young-adult onset of psychosis in schizophrenia, several of the behavioral abnormalities in mice display a post-pubertal onset and are corrected by acute antipsychotic drug treatment. In addition, poly(I:C) MIA offspring exhibit a postpubertal emergence of the hallmark structural abnormality in schizophrenia, ventricular enlargement (Li et al., 2009; Piontkewitz, Assaf, & Weiner, 2009).

Offspring of poly(I:C)-treated pregnant rats and mice have also been examined for neurochemical alterations. Adult offspring display increased levels of GABAA receptor α2 immunoreactivity (Nyffeler et al., 2006) and dopamine hyperfunction (Ozawa et al., 2006) as seen in schizophrenia, as well as a delay in hippocampal myelination (Makinodan et al., 2008). Expression of NMDA receptors in the hippocampus is reduced, as are the numbers of reelin- and parvalbumin-positive cells in the prefrontal cortex (Meyer et al., 2008c). Reduced dopamine D1 and D2 receptors in the prefrontal cortex and enhanced tyrosine hydroxlyase in striatal structures have also been reported (Meyer et al., 2008b). Although some of these changes are subtle and require replication, they are clearly relevant for schizophrenia.

Very little has been published on the electrophysiologic properties of neurons and circuits in poly(I:C) offspring. Recent work on hippocampal slices indicates that CA1 pyramidal neurons in the adult offspring of poly(I:C)-treated mothers display a reduced frequency and an increased amplitude of miniature excitatory postsynaptic currents. Although no difference is observed in paired-pulse facilitation or long-term potentiation (LTP) at Schaffer collateral-CA1 synapses, temporoammonic-CA1 synapses in the poly(I:C) offspring display a significantly increased sensitivity to dopamine (Ito et al., 2010). To assess hippocampal network function in vivo, expression of the immediate early gene, c-Fos, was used as a surrogate measure of neuronal activity. Compared to controls, the adult offspring of poly(I:C)-treated mothers display a distinct c-Fos expression pattern in area CA1 following novel object exposure. Because dopamine differentially influences object and spatial information processing in the hippocampus, these findings indicate that the offspring of immune-activated mothers may have an abnormality in modality-specific information processing (Smith et al., 2008; Ito et al., 2010).

Influenza infection and poly(I:C) are known to induce cytokines, so it was natural to ask if any of the cytokines induced by poly(I:C) MIA are involved in the changes in fetal brain development that result in neuropathology and abnormal behavior. Although cytokines are just one group of molecules that are induced by MIA, they are known to regulate various aspects of normal fetal brain development (reviewed by Deverman & Patterson, 2009). Thus, cytokine changes during MIA could perturb the delicate balance required for normal development. Apart from MIA’s relevance to schizophrenia, studies of the mechanism of MIA are important for understanding the many other deleterious effects that maternal infection can have on the fetus, such as those seen in periventricular leukomalacia and cerebral palsy. Two approaches have been taken in the investigation of cytokine effects: injecting or up-regulating cytokines during pregnancy in the absence of MIA, and blocking endogenous cytokines or preventing their induction during MIA. Investigation of cytokine mediation of maternal poly(I:C) effects on neuropathology and behavior in the offspring has focused on interleukin-6 (IL-6). Daily intraperitoneal injection of IL-6 in pregnant rats for three days results in profound effects on the offspring (Samuelsson et al., 2006). One hippocampal-dependent behavior—spatial memory in the water maze—was monitored in that study, and the IL-6-exposed adult offspring displayed increased escape latency and time spent near the pool wall. Thus, prolonged exposure to elevated IL-6 during fetal development causes a deficit in working memory, as is also seen in poly(I:C)-induced MIA. Remarkably, IL-6 mRNA levels in the offspring of mothers with prolonged IL-6 exposure remain elevated in the hippocampus of the offspring at four and 24 weeks of age. This is reminiscent of the permanent state of immune dysregulation in adult autistic and schizophrenia brains (Patterson, 2009). Further evidence of this parallel is the astrogliosis and elevated GFAP levels in the adult hippocampus of the IL-6-exposed offspring.

Although over-expression studies can be misleading with regard to endogenous ligand function, blocking endogenous IL-6 action during MIA supports the key role of this cytokine (Smith et al., 2007). Co-injection of a neutralizing anti-IL-6 antibody with maternal poly(I:C) blocks the effects of MIA on the behavior of the offspring (figure 10.1). Moreover, maternal injection of poly(I:C) in an IL-6 knockout mouse yields offspring with normal behavior. In addition to preventing the development of abnormal behaviors, the anti-IL-6 antibody also blocks the changes in brain gene transcription induced by maternal poly(I:C). The evidence that IL-6 is required to mediate the effects of poly(I:C) suggests that discovering where this cytokine acts could illuminate the molecular and cellular pathways that are involved in MIA-induced alterations in fetal brain development. Thus far, it is clear that poly(I:C)-induced IL-6 activates cells in both the placenta and the fetal brain (Hsiao & Patterson, 2011). Maternal injection of poly(I:C) induces downstream markers of IL-6 action (SOCS3 expression and the phosphorylation of STAT1 and STAT3) in the placenta and fetal brain. Induction of these markers requires IL-6, as shown by blocking experiments with an anti-IL-6 antibody. Immunohistochemical evidence indicates that the activation of the STAT and mitogen-activated kinase (MAPK) pathways occurs in the fetal side of the placenta. It is interesting that maternal poly(I:C) injection also induces the expression of IL-6 mRNA in both the fetal brain and the placenta, and this is also dependent on the IL-6 induced by maternal poly(I:C) (Meyer et al., 2006b; Hsiao & Patterson, 2011). This suggests a possible positive, feed-forward mechanism for chronic, subclinical inflammation in the brain. IL-6 protein as well as several chemokines are also induced in the placenta, and NFkB is activated (Koga et al., 2009). Poly(I:C) can induce cytokine and chemokine expression in a human trophoblast cell line in culture, showing that a direct effect is possible (Koga et al., 2009). Moreover, MIA activates the endogenous immune cells in the placenta, and alters placental endocrine status (Hsiao & Patterson, 2011).

The relevance of IL-6 for schizophrenia is further suggested by the fact that several extremely diverse risk factors identified by epidemiology converge to elevate maternal IL-6 (figure 10.2). In addition to IL-6, however, several other cytokines (IL-1α, IL-6, IL-10, and tumor necrosis factor α [TNF-α]) are elevated in the fetal brain by maternal poly(I:C) treatment (Meyer et al., 2006a), and cytokine expression in the neonatal offspring brain is also altered by MIA (Gilmore, Jarskog, & Vadlamudi, 2005). Conversely, genetically enforced expression of the anti-inflammatory cytokine IL-10 in macrophages attenuates the effects of poly(I:C) MIA, as measured by assays of PPI, latent inhibition, and open field anxiety in adult offspring (Meyer et al., 2008a). It is interesting that enhanced levels of IL-10 in the absence of MIA in pregnant mice leads to behavioral abnormalities in the adult offspring, illustrating the importance of the appropriate balance among cytokines that is required for normal development (Deverman & Patterson, 2009).

Figure 10.1. Abnormal behavior in MIA offspring is prevented by maternal treatment with anti-IL-6 antibody.
(Top panel) In the open field test, offspring of mice treated with poly(I:C) make fewer entries into the center than controls. Offspring of mice co-injected with anti-IL-6 and poly(I:C) enter the center as often as control mice. Offspring of mice co-injected with poly(I:C) and anti-IFNγ are not significantly different from those of controls or poly(I:C)-injected mice.
(Bottom panel) In the social interaction test, control mice show a strong preference for the social chamber, defined as (percent time in social chamber) - (percent time in opposite chamber), whereas the offspring of poly(I:C)-treated mice show no such preference. The deficit is corrected by maternal co-administration of IL-6 antibody along with poly(I:C).
[F3,50 = 4.244; p<0.01]; * < p<0.05 vs. control; #< p<0.05 vs. poly(I:C). Similar results were obtained with two other behavioral assays. (Reprinted with permission from Smith et al. [2007].)

Figure 10.2.Convergence on IL-6.
Extremely divergent environmental risk factors identified by epidemiologic studies can be linked by their common ability to raise IL-6 levels in the mother. It is also suggested that birth in winter or spring months and being born in an urban environment are related to the enhanced likelihood of maternal infection in those settings. Stress increases both serum IL-6 and susceptibility to infection. IL-6 is further implicated by animal studies that show its key role in both maternal poly(I:C) and lipopolysaccharide (LPS) models, as well as the observations that this cytokine is dysregulated in the brain in both schizophrenia and autism. (Source: Author.)

In addition to the brain, the peripheral immune system of poly(I:C) MIA off-spring is altered, as it is in schizophrenia. For instance, compared to controls, CD4+ T cells from the spleen and mesenteric lymph nodes of adult mouse MIA offspring display significantly elevated IL-6 and IL-17 responses to in vitro stimulation (Hsiao et al., 2010; Mandal et al., 2010). Furthermore, adult MIA offspring display reduced T cell responses to antigens specific to the central nervous system, despite elevated proliferation of nonspecific T cells (Cardon et al., 2009).

The maternal poly(I:C) model is also being used for postnatal therapeutic experiments. As already mentioned, acute antipsychotic medication administration can block several of the behavioral deficits in influenza infection and poly(I:C) MIA offspring. This has been taken a step further in experiments testing such medications in immature MIA offspring, before the onset of behavioral abnormalities and ventricular enlargement (Piontkewitz, Assaf, & Weiner, 2009; Meyer et al., 2010). Transient treatment for a week during this prodromal period during adolescence, many weeks before the onset of behavioral abnormalities and testing, is effective in preventing the emergence of abnormal behaviors as well as ventricular enlargement. This supports the notion that antipsychotic medication treatment of high-risk subjects is worthy of further investigation. It is notable, however, that clozapine treatment of offspring born to mothers injected with saline had a detrimental effect on the adolescent development of these controls, as assayed by behavioral tests (Meyer et al., 2010). Although the classic action of these antipsychotic medications involves blockade of the D2 dopamine receptor, it is worth noting in the present context that many of them can also influence cytokine expression (Pollmacher et al., 2000; Drzyzga et al., 2006).

The poly(I:C) model is also beginning to be used to explore gene-environment interactions, which is the dominant model of schizophrenia etiology. Two different mutant mouse strains of the leading schizophrenia candidate gene DISC1 are reported to be more sensitive to poly(I:C)-induced immune activation in the mother or in the neonatal pups than wild type controls (Abazyan et al., 2010; Ibi et al., 2010). Several different behavioral assays were used. Thus, there is a geneenvironment interaction worthy of further investigation. In addition, DISC1 null and heterozygote DISC1 pups born to poly(I:C)-treated heterozygote mothers display altered ultrasonic vocalizations compared to wild types (Malkova, Hsiao, & Patterson, 2010).

For expedience, all of the maternal poly(I:C) results discussed here have been summarized as if all of the laboratories are using the same protocol. In fact, some groups use mice and some rats, and some groups use intraperitoneal administration whereas others administer intravenously. Although most of the reports have yielded consistent results across laboratories, delivery site is potentially a complicating issue. It seems likely that intravenous delivery would provide access of poly(I:C) to the placenta at a higher concentration than would intraperitoneal delivery. Moreover, it is not clear whether poly(I:C) can cross the placenta. In addition, intraperitoneal delivery has the potential to more directly activate receptors in the mesenteric lymph nodes and the vagal afferents, sites important for sickness behavior and gastrointestinal responses. Various laboratories are using different salts of poly(I:C), and the manufacturers are not clear on the actual composition of the polymers they are providing. Another issue is that poly(I:C) is being injected at a variety of time points during pregnancy, and this is known to yield different results (see, for example, Meyer et al., 2006b). A final point concerns the diversity of behavioral responses observed within a treatment group, and even the diversity seen among the offspring in a single litter. This means that large numbers of animals are required for meaningful data and statistical differences between groups. But why should the behavior of individual offspring of a single mother differ significantly? One possibility is random epigenetic changes to the genome. Another explanation is related to position within the uterus, as there are known differences in placental physiology along the uterus (Ryan & Vandenbergh, 2002). Such heterogeneity of placental physiology could lead to differential responses to maternal infection and poly(I:C). Recall also that two-thirds of monozygotic human twins share the same placenta, which means that they are sharing key environmental factors that are not shared by most dizygotic twins (Patterson, 2007). This has implications for interpreting twin studies, where it is implicitly assumed that differences between monozygotic and dizygotic twins are due to genetics. All of these considerations also apply to the other animal models that will be discussed.

Another issue in all of these experiments is the potential effects of MIA on the behavior of the mother toward the pups during the early postnatal period. Cross-fostering MIA pups to surrogate control mothers does not prevent the onset of behavioral and neurochemical abnormalities in the offspring. Thus, these deficits are due in large part to the prenatal rather than postnatal effects. On the other hand, some abnormalities can be introduced in control pups raised by MIA mothers (Meyer et al., 2006b; Meyer et al., 2008b). Therefore, the behavior of the MIA mothers apparently is not completely normal. However, using the same immune-activated mother to raise her own litter is presumably more relevant to the real life situation.

Another animal model of MIA is based on the maternal bacterial infection risk factor. Lipopolysaccharide (LPS), a component of bacterial cell walls that acts through TLR-4, is injected into pregnant rats, mice, rabbits, or ewes, yielding offspring with many of the same behavioral abnormalities seen in the offspring of mothers with poly(I:C)-induced MIA (reviewed by Hagberg & Mallard, 2005; Jonakait, 2007; Meyer, Yee, & Feldon, 2007; Smith & Patterson, 2008; Meyer Feldon, & Fatemi, 2009; Patterson, 2009). This is not surprising, as ligands binding TLR-4 activate many of the same signaling pathways as TLR-3 ligands. Although the specific combination of cytokines and chemokines induced by TLR-4 is slightly different from that induced by TLR-3, both poly(I:C) and LPS produce a strong, transient immune activation. Some of the behavioral abnormalities shared between the poly(I:C) and the LPS model include PPI and social interaction deficits, increased anxiety, and abnormalities in dopamine-related behaviors (Borrell et al., 2002; Fortier et al., 2004; Golan et al., 2005; Hava et al., 2006; Romero et al., 2007). Other behavioral abnormalities in the LPS model include poor performance in the beam-crossing test, deficient object recognition, and impaired water maze spatial memory (Bakos et al., 2004; Lante et al., 2007; Coyle et al., 2009). Histologic findings in the LPS model include fewer, more densely packed neurons in the hippocampus; increased microglial and GFAP staining; altered tyrosine hydroxylase staining; decreased dopamine levels in the nucleus accumbens; decreased dendritic length; fewer oligodendrocyte precursors; and decreased myelin protein staining (Cai et al., 2000; Bell & Hallenbeck, 2002; Borrell et al., 2002; Carvey et al., 2003; Bakos et al., 2004; Ling et al., 2004; Golan et al., 2005; Elovitz, Mrinalini, & Sammel, 2006; Nitsos et al., 2006; Rousset et al., 2006; Wang et al., 2006b; Wang et al., 2007; Paintlia et al., 2008a; Paintlia et al., 2008b; Baharnoori, Brake, & Srivastava, 2009). These observations are largely consistent with schizophrenia neuropathology (Dean et al., 2009).

In one of the very few electrophysiologic studies of the offspring in the maternal LPS model, the intrinsic excitability of hippocampal CA1 pyramidal neurons was reported to be elevated and, whereas paired-pulse facilitation of the fEPSP is attenuated, long-term potentiation is normal (Lowe, Luheshi, & Williams, 2008). The authors suggest that there is a reduction in presynaptic input to CA1, with a compensatory elevation of postsynaptic glutamatergic responses. These results appear to be different from those observed in the poly(:C) model previously discussed here.

Although little attention has been paid to neurogenesis in the MIA models, maternal LPS, particularly when administered late in gestation, results in slightly fewer BrdU+ cells generated immediately after LPS (Cui et al., 2009). A larger deficit is observed in BrdU+ cells generated on postnatal day 14, and it persists for four subsequent weeks. In light of the deficit in migration to layer 2/3 observed in the poly(I:C) model, it would also be interesting to examine the migration of the newborn neurons in the LPS model.

In common with findings in the neonatal offspring of the poly(I:C) and multiple IL-6 injection models are observations of fetal and neonatal brain inflammation in maternal LPS offspring, as defined by astrogliosis (enhanced GFAP staining), altered microglial immunostaining, positron emission tomography (PET) imaging, and increased expression of proinflammatory genes such as IL-6, TNF-α, or interferon-γ (IFN-γ) (Bell & Hallenbeck, 2002; Borrell et al., 2002; Bell, Hallenbeck, & Gallo, 2004; Elovitz et al., 2006; Liverman et al., 2006; Nitsos et al., 2006; Rousset et al., 2006; Kannan et al., 2007; Paintlia et al., 2008a; Paintlia et al., 2008b; Salminen et al., 2008). Inflammatory cytokines are also induced in the placenta (Silver et al., 1997; Urakubo et al., 2001; Bell, Hallenbeck, & Gallo, 2004; Gayle et al., 2004; Ashdown et al., 2006; Elovitz & Gonzalez, 2008; Paintlia et al., 2008a; Paintlia et al., 2008b; Salminen et al., 2008). The evidence of inflammatory changes in the brains of offspring of LPS-treated mothers is consistent with the striking findings of immune dysregulation in human schizophrenia. The level and types of inflammatory markers reported for fetal brain and placenta vary, depending in part on the age, number, and site (peritoneum, cervix, uterus, or amniotic fluid) of the maternal LPS injections. An LPS protocol of maternal intra-peritoneal injections every other day induces a permanent inflammatory state, as shown by elevated IL-6 and other proinflammatory cytokines in sera of adult offspring (Romero et al., 2007). Maternal LPS administration can also lead to altered responses to inflammatory challenge in adulthood (Wang et al., 2006b; Hodyl et al., 2007; Lasala & Zhou, 2007). It is interesting that the cytokine elevation in adult serum can be prevented by antipsychotic drug administration (Romero et al., 2007), as was found in the poly(I:C) model, already mentioned here. Confirming the innate inflammatory pathway in nonhuman primates, the TLR-4 antagonist TLR4A blocks the effects of intra-amniotic, LPS-induced cytokines and uterine contractions (Adams Waldorf et al., 2008).

How does maternal LPS alter fetal brain development? As with maternal poly(I:C), there is evidence of activation of inflammatory pathways in both placenta and fetal brain. The latter reaction presumably is indirect, as labeled LPS does not cross the placenta, at least when injected at E15 in the rat (Ashdown et al., 2006). A similar labeling experiment with poly(I:C) has not been reported as yet. Because cytokines can cross the placenta, at least at some stages of development, and they can be generated by the placenta, these molecules have been investigated as mediators of the effects of maternal infection on fetal brain development. Injection of anti-TNF-α antibodies or an inhibitor of TNF-α synthesis (pentoxifylline) can reduce maternal LPS-induced fetal loss and growth restriction. Conversely, injection of TNF-α alone can induce fetal loss (Silver et al., 1994; Xu et al., 2006). These effects are exacerbated significantly in IL-18 knockout mice, but not in IL-1α/α knockout mice (Wang et al., 2006a). Experiments with double knockout mice demonstrate that both TNF and IL-1 signaling are important in bacterially induced preterm labor (Hirsch, Filipovich, & Mahendroo, 2006). As in the poly(I:C) model, IL-10 is protective, mitigating white matter damage caused by maternal E. coli infection (Pang et al., 2005). An attractive feature of this potential therapeutic agent is that endogenous IL-10 is essential for resistance to LPS-induced preterm labor and fetal loss. Thus, administration of this cytokine enhances a natural protective mechanism by attenuating the production of proinflammatory cytokines in the uterus and placenta (Rivera et al., 1998; Terrone et al., 2001; Robertson, Skinner, & Care, 2006). Subcutaneous administration of IL-10 is nontoxic in long-term studies in mice and monkeys, although testing was not done during pregnancy (Rosenblum, Johnson, & Schmahai, 2002). It is important to note, however, that enhanced levels of IL-10 in the absence of MIA in pregnant mice leads to behavioral abnormalities in the adult offspring (Meyer et al., 2008c). Moreover, IL-10 administration can impair the response to infection (van der Poll et al., 1996). Thus, “only when the pathogenesis of obstetrical complications is more fully understood can meaningful therapeutic interventions become a realistic goal” (Elovitz, 2006). The role of IL-6 has not been investigated thoroughly in the maternal LPS model, but this cytokine is important in the neonatal brain response to intracerebral injection of LPS. An anti-IL-6 antibody attenuates ventricle dilation as well as astrocyte and microglial activation, and it improves behavioral outcome (Pang et al., 2006).

The importance of a cytokine imbalance following MIA could also be relevant postnatally. It is clear from both animal and clinical studies that acute changes in cytokines can markedly affect behavior, even to the point of inducing psychosis (reviewed by Bauer, Kerr, & Patterson, 2007). Such an imbalance could perhaps explain a series of puzzling case studies reporting the sudden onset of autistic symptoms in children and adults following encephalitis or infection with herpes simplex, varicella, or cytomegalovirus (Libbey et al., 2005). Central nervous system infections of this type are known to induce proinflammatory cytokine expression rapidly. In contrast, infections in autistic children are associated with acute amelioration of behavioral symptoms, which is also consistent with ongoing regulation of behavior by cytokines (Curran et al., 2007). Relevant to schizophrenia, there are reports (from another era) that malarial infection can ameliorate psychosis (Tempelton & Glas, 1924; Hinsie, 1929). A key point about the hypothesis of cytokines directly inducing or influencing behavior postnatally is that it raises the possibility of developing treatments based on anti-cytokine or anti-inflammatory agents. In fact, a preliminary study in 25 autistic children of the anti-inflammatory thiazolidinedione pioglitazone revealed a significant decrease in irritability, lethargy, stereotypy, and hyperactivity, with greater effects on the younger patients (Boris et al., 2007). Anti-inflammatory medication trials have also been proposed for schizophrenia (Riedel et al., 2005; Potvin et al., 2008), although the initial results have been mixed (Stolk et al., 2007). As already mentioned here, antipsychotic medications can influence cytokine expression, induce fever, and attenuate the peripheral cytokine response to poly(I:C) MIA.

Oxidative stress may also play an important role in the response to MIA, as pretreatment with the antioxidant N-acetylcysteine (NAC) prevents LPS-induced markers of stress in male fetuses and subsequent deficits in hippocampal long-term potentiation and water maze performance (Lante et al., 2007). Treatment with NAC also attenuates the induction of IL-6 in fetal blood (Beloosesky, Gayle, & Ross, 2006) as well as cytokine induction and leukocyte infiltration in the placenta (Paintlia et al., 2008a; Paintlia et al., 2008b). Various forms of prevention and treatment in the context of MIA are illustrated in figure 10.3.

Another version of the LPS model involves direct injection of LPS into the fetus, as reviewed by Wang et al. (2006b). This approach bypasses the effects of LPS on the placenta and maternal host, both of which may be critical for the development of pathology in the fetus. The same is true for models involving injection of LPS, viruses, poly(I:C), or cytokines during the early postnatal period (Pearce, 2003; Nawa & Takei, 2006; Wang et al., 2006b). Moreover, it is not clear that infection in the neonatal period increases risk for schizophrenia. The rationale for the neonatal injection models is that the very early postnatal rodent brain is thought to be at a stage of development similar to that of the human brain in the second or third trimester. However, the most recent epidemiologic data indicate that the periconceptional period and the first and early second trimesters may also represent a critical window for exposure to certain maternal infections that lead to risk for schizophrenia (Brown & Derkits, 2010). Another factor to consider is the timing of immune system development. In primates, the immune system develops primarily in utero; in rats and mice, a major proportion of this development occurs during late gestation and the early postnatal period (Merlot, Couret, & Otten, 2008).

Figure 10.3. Potential prevention, intervention, and treatments for maternal infection.
A timeline is depicted illustrating some of the attempts at blocking or diminishing the effects of maternal infection. Successful anti-influenza vaccination before pregnancy would be an effective and safe strategy, although it would not prevent other types of maternal infection. Vaccination during pregnancy is strongly recommended by public health authorities, although doubts have been raised about both its efficacy and its safety. Other immunobiological approaches include the use of modified bacterial toxins that are nontoxic but elicit production of antitoxins (as for diphtheria and tetanus), polysaccharides used as adjuvants (as for meningococcus), and recombinant Ig protein (as for hepatitis). Antimicrobial drugs could be used either as a preventative measure or following signs of infection. Safety for the fetus is a possible issue, however. There are a number of approaches for mitigating infection-driven inflammation, including nonsteroidal anti-inflammatory drugs (NSAIDs), N-acetyl cysteine (NAC), anti-inflammatory cytokines (AICs) (e.g., IL-10), and cytokine blockers (e.g., antibodies against IL-6, TNF blocker). All but the NSAIDS have proved effective in rodent LPS or poly(I:C) models. However, their utility under the conditions of actual maternal infection is a key issue because of the possibility of disturbing the proversus anti-inflammatory balance that is essential for a healthy pregnancy. A different approach that is currently being tested in the poly(:C) model involves supplementing choline in the diet of the mother—this is also being tested in human pregnancies at risk for schizophrenia outcome. Because there are clear signs of immune dysregulation in the brains and cerebral spinal fluid (CSF) of schizophrenia and autistic patients, anti-inflammatory approaches are being tested postnatally, either before or following the onset of symptoms. Antipsychotic drugs are proving effective during the prodromal period in preventing symptom onset in the poly(I:C) model, and could be acting to mitigate inflammation as well as blocking the dopamine receptors in the central nervous system. Recent experiments are also testing the utility of probiotic bacteria in preventing abnormal behaviors in the poly(I:C) model. The efficacy of these approaches following symptom onset remains to be proved. (Illustration by Elaine Hsiao.)

Bacterial infection is associated with schizophrenia (Sorensen et al., 2009), and obstetric complications caused by such infections increase the risk for schizophrenia (Byrne et al., 2000). Intrauterine infections are associated with very low birth weight, which is correlated with neurologic disorders. Among the microorganisms isolated from the preterm placenta are gram-negative bacteria that are known to be involved in periodontal disease, F. nucleatum, C. rectus, and P. gingivalis. Moreover, epidemiologic evidence links periodontal disease with premature delivery (Bobetsis, Barros, & Offenbacher, 2006). In a pregnant mouse model, intravenous injection of F. nucleatum results in premature delivery and stillbirth (Han et al., 2004), and the infection is confined to the uterus. Fetal loss is reduced in TLR4-deficient mice and by administration of the TLR4 antagonist, TLR4A. It is interesting that TLR4A reduces fetal death and placental (decidua) necrosis without affecting bacterial colonization of the placenta, indicating the critical involvement of inflammation (Liu, Redline, & Han, 2007). Subcutaneous infection with C. rectus or P. gingivalis induces markers of inflammation in the placenta and amniotic fluid, as well as fetal growth restriction (Lin et al., 2003a; Lin et al., 2003b; Offenbacher et al., 2005; Yeo et al., 2005; Bobetsis, Barros, & Offenbacher, 2007). In an alternative mouse model using systemic administration of P. gingivalis, fetal growth restriction is observed in every litter, but not in every fetus. It is important that P. gingivalis DNA is found only in the placentae of affected fetuses and that those placentae show elevation of proinflammatory and reduction of anti-inflammatory cytokines (Lin et al., 2003a). These results link cytokines with fetal morbidity, and they highlight the importance of heterogeneity among placentae within the same uterus. Placental status is a key issue in interpreting genetic heritability in twin studies of schizophrenia (Patterson, 2007). An alternative model with more construct value involves oral infection of mice with C. rectus, P. gingivalis, or both. The mice are then mated. Examination of the placentae reveals elevated TLR4 expression in the trophoblasts, with reduced fetal weight (Arce et al., 2009).

Although there are as yet no published studies of the behavior of the offspring of mice infected with periodontal bacteria, brain neuropathology has been observed. In a preliminary report, myelin defects are seen in the corpus callosum, hippocampus, and cortex of neonatal mouse offspring of C. rectus-infected mothers (Offenbacher et al., 2005).

There are also a few papers on intrauterine infections with E. coli during late pregnancy. This results in microglial or macrophage infiltration or activation, astroglial activation, and reduced staining with myelin markers in the fetal brain.

As mentioned previously, these signs of inflammation and white matter damage are attenuated by intravenous administration of IL-10 the day after maternal infection (Pang et al., 2005). This finding is similar to the anti-inflammatory effects of IL-10 in the studies of LPS and poly(I:C) administration. Studies of gram-negative bacterial infections and TLR4 are directly relevant to the work using maternal LPS, as LPS is expressed by gram-negative bacteria and activates TLR4.

Although mouse models have the benefit of genetic manipulation, nonhuman primates display behaviors that are much more homologous to those in humans. Therefore, it would be of particular interest to evaluate behavior in nonhuman primate MIA models. However, as in schizophrenia, the key behavioral changes may have a postpubertal onset, making the experiments long-term and expensive. A preliminary MRI analysis of the effects of influenza infection in pregnant rhesus monkeys reports that the one-year-old offspring display small but significant reductions in cortical gray matter (Short et al., 2010). The largest reductions are in cingulate and parietal areas, and a slight reduction in white matter volume is seen in the parietal cortex. These offspring spend less time with their mothers than controls do, yet they emit more stress-related vocalizations. In this experiment, the early third trimester was chosen as the time of infection, which has generally not been shown to be within the window of vulnerability for the maternal infection risk factor for schizophrenia. An alternative approach is also under way, using multiple injections of poly(I:C) in rhesus monkeys during the late first trimester (Baughman et al., 2011).

It is important that the poly(I:C) and LPS models display many key features of schizophrenia neuropathology (particularly the enlarged ventricles seen with poly(I:C)), and that these models display a variety of behavioral abnormalities that resemble the negative symptoms of schizophrenia. However, these endophenotypes are shared with many other disorders. More specific to schizophrenia are the positive symptoms, such as hallucinations, although these can also be found in bipolar and major depressive disorders. However, this is generally considered to be a uniquely human trait or impossible to assay in animals. Nonetheless, there is a definition of hallucination that should be possible to investigate in animal models: the appearance of neuronal activity in a sensory cortex in the absence of external sensory input. This activity should also be evoked by administration of known hallucinogenic drugs and be blocked by 5-HT_2A receptor antagonists. Part of this paradigm has, in fact, already been achieved: injection of the hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI) intraperitoneally in adult mice induces immediate early gene (IEG) expression in sensory cortices in the absence of external sensory stimuli (Malkova, N. & Patterson, P. H., unpublished data; also Gonzalez-Maeso et al., 2007). Such gene expression is often taken as a surrogate marker of neuronal activity. The IEG+ neurons also express 5-HT_2A receptors (Gonzalez-Maeso et al., 2007).

Also relevant in this context is a mouse model of Wernicke-Korsakoff syndrome, which is a neuropsychiatric disorder that includes hallucinations, among a variety of other symptoms. This model is established by thiamine deprivation, as is the case in the human disorder. These mice display an elevated sensitivity to intracerebral DOI administration, as measured by increased head twitches (Nakagawasai et al., 2007). This provides an example of elevated sensitivity to a hallucinogen in a mouse model of a human disorder that involves hallucinations.

Given that influenza viruses mutate frequently, effective vaccination must be administered each year. Because maternal infection carries risk, it is widely recommended that women who become pregnant during or just before flu season receive the vaccine for that current year. As the animal work indicates that MIA in the absence of a pathogen is sufficient to mimic the effects of infection on the fetus, an obvious question is whether vaccination provides sufficient MIA to mimic the effects of poly(I:C) or LPS. Epidemiologic studies of human maternal vaccination do not necessarily provide a clear answer about its risk-benefit balance (Ayoub & Yazbak, 2008; Mak et al., 2008; Skowronski & De Serres, 2009); therefore, more animal work on maternal vaccination is warranted.

Current work quoted from the author’s laboratory is supported by grants from the National Institutes of Mental Health and General Medical Sciences, the Binational Science Foundation, the Caltech Brain Imaging Center, the Della Martin Foundation, Autism Speaks, and the Simons Foundation. Thanks to Elaine Hsiao for figure 10.3, to Patric Prado and Alan Brown for helpful comments on the manuscript, and to Laura Rodriguez for editing assistance.

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