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Clues Emerge About the Maternal Infection Risk Factor for Schizophrenia

15 February 2011. Studies suggest that mothers who are infected with various pathogens during pregnancy pass an unfortunate legacy on to their children: an increased risk of schizophrenia. Most animal studies exploring this issue have modeled infection by exposing mouse dams to polyriboinosinic-polyribocytidylic acid, a viral mimic better known as poly I:C. Javier González-Maeso and colleagues at the Mount Sinai School of Medicine in New York City took a different approach: they infected mice in their first trimester of pregnancy with a mouse-adapted H1N1 virus. Their paper in the February 2 issue of the Journal of Neuroscience describes the changes they observed in the adult offspring of infected mice. Citing parallels in the schizophrenia literature, the researchers report upregulation of serotonin 5-HT2A receptors and downregulation of metabotropic glutamate mGlu2 receptors in the frontal cortex; they also found a heightened sensitivity to hallucinogens.

Many infections, same outcome
This research fits within a larger set of hypotheses about infectious and immune factors in schizophrenia etiology (see SRF related news story; SRF news story; SRF news story; SRF news story). It builds on longitudinal epidemiological studies that link schizophrenia to maternal exposure to infections of various kinds, including the flu, cytomegalovirus, herpes simplex virus type 2, bacteria, and the parasite Toxoplasma gondii (for reviews of this field, see Brown and Derkits, 2010). In an interview with SRF, Paul Patterson, California Institute of Technology in Pasadena, said that the variety of infections associated with schizophrenia suggests that “it’s the mother’s response that’s important, not the specific kind of infection.” That response seems to include the release of cytokines, signaling proteins secreted by cells of the immune system (for more about the role of cytokines, see Patterson, 2009).

To explore the mechanisms by which maternal infections might foster schizophrenia, researchers have turned to animal models in which they activate the mother’s immune system by exposing her to infectious agents or to other substances that trigger the same kind of cytokine release as a viral or bacterial infection would. Such substances include lipopolysaccharide (LPS), a bacterial endotoxin, and poly I:C. As for the latter, Meyer and Feldon (Meyer and Feldon, 2011) see the poly I:C approach as “a very powerful neurodevelopmental animal model of schizophrenia-relevant brain disease.”

A roundup of recent findings
Researchers have been using cytokine-releasing agents to examine schizophrenia-related abnormalities in the offspring of immune-activated mothers and to seek clues to how infections might promote schizophrenia. For example, in a study by Dickerson and others (Dickerson et al., 2010), rats whose mothers had received one injection of poly I:C while pregnant with them showed altered synchrony between cortical regions in adulthood, reminiscent of the changes seen in schizophrenia (see SRF Current Hypothesis by Woo and colleagues). Using the same model, Ito and colleagues (Ito et al., 2010) found that the adult offspring of mice challenged with poly I:C showed evidence of abnormal hippocampal processing at the synaptic and behavioral levels. The offspring performed poorly at processing information about objects, as opposed to locations. The researchers suspect that dopamine abnormalities play a role.

In Switzerland, Bitanihirwe and colleagues (Bitanihirwe et al., 2010) report alterations, some sex-specific and some not, in basal levels of the neurotransmitters dopamine, glutamate, γ-aminobutyric acid, and glycine in cortical areas in mice whose mothers were exposed to poly I:C. This echoes earlier findings last year from this group (Vuillermot et al., 2010; Bitanihirwe et al., 2010) and from the O’Donnell group, who used an LPS challenge (Feleder et al., 2010). Both groups concluded that infection during pregnancy affects the development and function of dopaminergic signaling in the offspring of immune-activated mothers.

Baharnoori and associates (Baharnoori et al., 2010) pushed the analysis earlier than most studies, which examined adult offspring. In rats born of LPS-exposed mothers, they noted subtle behavioral changes soon after birth and changes in serotonin receptor gene expression in the cortex at postnatal day 3. In a poly I:C study, De Miranda and colleagues (De Miranda et al., 2010) found that maternal immune activation causes neuronal stem cell abnormalities in the mouse embryo by way of Toll-like receptors, which govern the mother’s immune response.

Because mice cannot report hallucinations
In the wake of these studies, González-Maeso, first author José Moreno, and others explored the biochemical correlates of the abnormal behaviors seen in the offspring of virus-infected mothers. They focused on serotonin 5-HT2A receptors and metabotropic glutamate mGlu2 receptors. The serotonin receptors play a role in the effects of hallucinogenic drugs, which can induce behavioral changes that resemble schizophrenia and, with enough use, may even cause psychosis. Some researchers think that mGlu2/3 receptor agonists show promise as a schizophrenia treatment (see SRF related news story; SRF news story).

In the new study, Moreno and colleagues challenged the immune systems of pregnant mice on day 9.5 of their pregnancy, which corresponds to the end of the first trimester in humans. Mice generally do not get the flu, but the researchers exposed them to a mouse-adapted H1N1 virus, causing a flu-like illness in the mice. A second group of pregnant mice received the vehicle only. After the mothers gave birth, the researchers waited until the pups reached adulthood to learn how maternal immune activation had affected them.

Patterson told SRF that Moreno and colleagues make the “very important” contribution of “looking at what I would call the rodent equivalent of hallucinations.” While other studies have assayed the so-called negative symptoms of schizophrenia, Moreno and colleagues looked at “activation of the sensory cortex in the absence of sensory input, mimicked by injecting a hallucinatory drug.”

The Mount Sinai team injected the offspring of viral- or mock-infected mice with either the hallucinogenic 5-HT2A agonist DOI (1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane) or vehicle alone. They noted that the offspring of infected mothers showed increased sensitivity to the drug, as shown by a greater head-twitching response. “Notably, our results demonstrate that alterations in the head-twitch behavioral response are only observed after puberty in prenatally infected mice—a finding that parallels the adult onset of the disease in humans and supports our mouse schizophrenia model of perinatal insult,” the researchers write.

Maternal infection also amplified the response of cortical neurons to DOI, as shown by greater expression of the genes c-fos, egr-1, and egr-2, which serve as markers of neural activity.

The study also looked at noncompetitive NMDA glutamate receptor antagonists, including MK-801, which change animal behavior in ways that echo the positive symptoms, negative symptoms, and sensorimotor gating deficits seen in schizophrenia. MK-801 increased locomotion, as expected, but it did so similarly in the offspring of infected versus uninfected mothers. LY379268, an mGlu2/3 agonist, reduced its effects, but only in mice born of uninfected mothers.

Delving deeper, Moreno and colleagues found that mice born of virus-infected mothers had increased density of 5-HT2A receptors and a lower density of mGlu2/3 receptors in the frontal cortex. They also noted unusually high expression of 5-HT2A mRNA and low expression of mGlu2 mRNA in that group, which showed normal expression of 5-HT2C and mGlu3 mRNA. These results dovetail with earlier Mount Sinai findings in untreated humans with schizophrenia that fingered similar serotonin and glutamate receptor changes in the disease (see SRF related news story).

The changes seen in the offspring of infected mothers did not seem to reflect infection of the fetus: only two of the 31 youngsters showed an antibody response to the virus. “Together with the absence of detectable virus in embryo samples, these data also suggest that the changes observed in the offspring are a consequence of maternal response to viral infection, and not of direct fetal infection by mouse-adapted influenza virus,” Moreno and colleagues wrote.

This conclusion receives support from another study that used the H1N1 virus. Fatemi and colleagues (Fatemi et al., 2011) found that infection at embryonic day 7 led to structural and gene expression changes in the placenta, as well as altered gene expression in the hippocampus and prefrontal cortex of exposed offspring. Neither the placentas nor the brains showed signs of active infection, again fingering the mother’s immune response rather than the infection itself.

In the future, Patterson would like to see studies that examine genetic risk in conjunction with environmental risk factors like maternal infection. Given the small effect sizes for most mutations, he wonders whether they have to combine with an environmental insult to cause schizophrenia. “The effect size of maternal infection is much greater than virtually all of the mutations that have been found, so I think the epidemiology deserves a lot more attention than it has been getting,” he said.—Victoria L. Wilcox and Hakon Heimer.

Reference:
Moreno JL, Kurita M, Holloway T, López J, Cadagan R, Martínez-Sobrido L, García-Sastre A, González-Maeso J. Maternal Influenza Viral Infection Causes Schizophrenia-Like Alterations of 5-HT2Aand mGlu2 Receptors in the Adult Offspring. J Neurosci. 2011 Feb 2;31(5):1863-72. Abstract

Q&A With Paul Patterson. Questions by Victoria L. Wilcox

Q: As you think about the research looking for biological mechanisms that could transduce maternal infection into risks for schizophrenia, what do you think are the major insights of the field so far?

A: In terms of the mechanism of how maternal infection alters fetal brain development, the first thing to say is that it's not caused by infection of the fetus, but rather it's caused by the activation of the mother's immune system. In their recent paper (Moreno et al., 2011), Moreno and colleagues provide some evidence in favor of that—that is, they don’t see evidence of the virus in the fetus, but that's been published previously by us (Shi et al., 2005). I think the most compelling evidence, though, is that you can get very similar, maybe the same, behavioral abnormalities in the offspring without using the virus at all; you can just activate the mother's immune system. And we do that with double-stranded RNA, poly I:C, without a pathogen. It should be noted that the behavioral abnormalities are consistent with those seen in schizophrenia, but many of them are also consistent with symptoms in autism. This is not surprising, because maternal infection is a risk factor for both schizophrenia and autism. There was an important study in 2010 that analyzed over 10,000 cases of autism in the Danish medical registry and found an association with viral infection in the first trimester (Atladóttir et al., 2010). This is similar to findings by Alan Brown and colleagues in schizophrenia, where they found the risk factor for infection was likely to be in the late first, early second trimester (Brown et al., 2004). In the schizophrenia epidemiology, the infections can be of almost any kind; there's evidence for viral, bacterial, and parasitic toxoplasma infections as increasing risk. This is also consistent with the idea that it's the mother's immune response that's important, not the particular kind of infection.

Q: What are some of the challenges to this field? Can they be overcome and, if so, how?

A: On the behavioral side, of course, you're dealing with mice or rats, which have only analogous behaviors to those in humans. In that sense, the behaviors that we and others look at are consistent with those in human schizophrenia and autism, but, of course, these are rodent behaviors. In that sense, Moreno et al. provide a new piece of data that is, I think, very important, which is they provide evidence for what I call the rodent equivalent of hallucinations. They see activation of the sensory cortex, in the absence of sensory input, which can also be evoked by injecting a hallucinatory drug. The surrogate marker for neuronal activation that they use is early gene activation. The hallucinogenic drug induces these genes in the cortex, but the key point is that there is a stronger induction in the offspring of mothers who were infected compared to controls. This is what is seen in schizophrenia: schizophrenics are more sensitive than controls to hallucinogens. Moreno further reports that the behavioral response to hallucinogens is also greater in the offspring of infected mothers. Our group has unpublished data very similar to these using the poly I:C maternal immune activation model. A key point about this rodent version of hallucinations is that it is a behavior that one can measure in rodents that is more specific to schizophrenia than other behaviors that we and others have measured. Hallucinations can also be found in bipolar disorder, but they are very prominent in schizophrenia. This is a so-called positive symptom, rather than a negative symptom, which is what everybody is assaying normally.

Q: I'm glad you mentioned poly I:C because that leads into my next question. The Moreno study uses “mousified” influenza virus, whereas a lot of the studies seem to use poly I:C to simulate the flu. What are the pros and cons of the different approaches?

A: The influenza model is more like the human situation, where one is studying an actual infection of the mother. The poly I:C approach has the advantage that one can control the timing of the mother’s immune response very precisely, whereas in the infection, the mother is sick for many days after infection—in other words, for a good part of embryonic development. In contrast, the poly I:C drives up the cytokines in the mother very transiently, so one is looking at a very narrow time window of the effect. Also, one can control the dose very closely with poly I:C, while it is harder to control the dose with infection of the virus, which is dependent on the breathing pattern of the animal. One can use different concentrations of the virus, but it is never clear what dose the animal is actually absorbing in the respiratory tract. We've done infection with different doses of influenza virus, and we do see a dose-response curve in the behavior of the offspring, but it's difficult to specify exactly what dose the mouse is getting. Nonetheless, the cytokine response to poly I:C is certainly not identical to influenza infection.

Q: What stands out to you about the results of the Moreno study?

A: I mentioned that, to my mind, the most interesting result is the evidence that the offspring of infected mothers are more sensitive to the hallucinogen. They also report that there are changes in the serotonin and glutamate receptors in the brains of the offspring, which is useful, and adds to the neuropathological findings of others in this model.

Q: What do the results imply about the role of glutamate and serotonin in the relationship between the infection in the mother and schizophrenia in her offspring, and is that important in terms of the neuropathology?

A: Moreno et al. make the point that they think the change in these receptors might be related to the behavioral changes that are observed in the offspring, which could be true. One would have to, of course, investigate that in much more detail to see if there's really a relationship between changes in, say, a glutamate receptor and the behaviors.

Q: Are there any limitations or caveats about the study that are important to keep in mind?

A: I don't think it's a terribly important part of the paper, but the negative result that they do not detect the virus is not as compelling as the positive result that similar behaviors can be observed in the offspring without using a virus; one can just stimulate the immune system in the mother.

Q: This is a mouse model, and some people are skeptical of them. Obviously, there are differences and similarities between mice and humans, so what, if anything, does this study based on a mouse model mean for humans with schizophrenia? What's needed to connect those dots?

A: A key advantage is that, in the rodents, one can study the mechanism of how maternal infection alters fetal brain development—this can't be done in humans.

Q: You can't just infect pregnant women with a virus, for instance.

A: What's known so far is that it's the mother's immune response that's important. Second, we found that the rise in the cytokine interleukin-6 that occurs during infection is critical for the changes in behavior of the offspring. If one blocks the interleukin-6 response, you don't see the abnormal behaviors in the offspring. Conversely, if one simply injects IL-6 alone in pregnant mice, the abnormal behaviors are found in the offspring, so you don't need poly I:C or the virus; transiently increasing this cytokine is sufficient. Another point about the mechanism is that the placenta is at least one of the sites of action of the maternal immune response (Hsiao and Patterson, 2010). Cytokines are upregulated in the placenta, there are endogenous immune cells in the placenta that are activated, and this results in endocrine changes in the placenta that undoubtedly affect the fetus. In addition, maternal poly I:C administration (or maternal LPS, to mimic bacterial infection) increases cytokine levels in the fetal brain, and these changes are prolonged until at least the early postnatal period (see Patterson, 2009). In other words, the first steps are being taken toward understanding the cellular and molecular pathways of how maternal infection alters fetal brain development, which ultimately changes behavior. That's one point: the mechanism. Another feature of animal work is the ease of testing potential therapeutics. For example, the Meyer group in Zurich and the Weiner group in Tel Aviv recently published important papers on one type of intervention, which is treating adolescent offspring of immune-activated mothers with antipsychotic drugs before they exhibit certain behavioral abnormalities and neuropathology (Meyer et al., 2010; Piontkewitz et al., 2010). This prevents the onset of at least some of the abnormal behaviors and neuropathology, in particular, the enlargement of the ventricles, which is a cardinal neuropathology in schizophrenia. This, I think, adds fuel to the fire concerning the question of prodromal treatment of teenagers at extremely high risk of schizophrenia. Many people argue that such treatment is ineffective or perhaps even unethical, but the rodent results, both in rats and mice, are very compelling that adolescent treatment can prevent abnormal behavior and pathology in the offspring. Such results also suggest that other novel treatments could be tested in these offspring because, clearly, not all the abnormal behaviors are permanently set during embryonic development. One might have predicted that since fetal brain development is altered, it's too late to do anything postnatally. These results indicate otherwise.

Q: Are there any other potential approaches to treatment or some kind of preventive intervention that could occur prior to the prodrome, such as vaccinating the mothers?

A: We're particularly interested in modulating the immune system of the offspring in the early postnatal period. That's another place that is potentially important, particularly in autism, because you would like to intervene in autism as early as possible. Since the offspring of infected or immune-challenged mothers display the cardinal symptoms of autism, which we haven't talked about yet, you could test early interventions. These symptoms are 1) repetitive or stereotyped behaviors; 2) deficits in communication, which in the animals is tested by recording ultrasonic vocalizations; and 3) deficits in social interaction. These behaviors can be readily assayed in the rodents and have parallels in human autism. There's also a neuropathology that's commonly found in autism, which is a localized deficit in Purkinje cells. Regarding maternal vaccination, one issue arises from the CDC recommendation that all pregnant women be vaccinated for the flu. The rodent results raise the question: Is this really safe? Vaccination activates the immune system, and that's what poly I:C does. In my mind, it raises the quantitative question: Is vaccination strong enough to activate the mother's immune system to the extent that it could alter fetal brain development as we see in the mice with poly I:C or IL-6 injection?

Q: That's a sobering thought.

A: And this hasn't been clarified. In fact, a review by the Canadian CDC flu experts (Skowronski and De Serres, 2009) concludes that it is not yet clear that maternal vaccination is both safe and effective. It seems that more studies need to be done. In fact, the studies that are quoted by the U.S. CDC regarding maternal vaccination did not look for schizophrenia in the offspring, because, of course, that would involve following people for 20 or more years.

Q: Interesting. Is there anything else you want to say regarding what are the biggest unanswered questions that remain in the field?

A: In terms of the mechanism of how maternal infection changes fetal brain development, we're only taking the very first small steps to understanding that. We don't know what the cytokines do in the fetal brain; we're not exactly sure where they're acting, or which are the key changes in brain development that lead to abnormal behaviors. There are many, many steps between changes in fetal brain development and actually seeing how that plays out in behavior. In fact, that will be very difficult to do because the behaviors that we're looking at are complicated. There is also a lot to be done in terms of testing potential new treatments for both the autism- and the schizophrenia-like behaviors and pathology.

Q: Do you think the findings from the Moreno study and other studies exploring this area could lead to a treatment?

A: There's nothing in the Moreno study that speaks to that question directly, but the results on the antipsychotic drugs show that you can test the drugs, and you can get effects, so the field is wide open for that.

Q: Is there anything I haven't asked you about that you would like to say about this topic, about research in this area, or about the Moreno study in particular?

A: Two points: First, I think everybody recognizes the importance of genes in schizophrenia and autism, but the animal studies that we're talking about so far don't really speak to the question of genetic risk. Therefore, another area of future work that's very important is to combine the susceptibility genes with the environmental risk factors, such as maternal infection. There have been a couple of studies on this published so far, but there's much more that can be done. People have looked at maternal immune activation combined with the DISC1 gene knockout (Abazyan et al., 2010). There's also a recent paper from Dan Ehninger and Alcino Silva on the tuberous sclerosis mouse model (Ehninger et al., 2010). Mutations in the tuberous sclerosis genes can enhance the chance of developing autism features. This paper shows a synergism between the poly I:C environmental factor and the tuberous sclerosis mutation.

Q: So there could be some gene-environment interactions involving maternal infection and perhaps some gene that makes humans or animals more vulnerable.

A: Right. This hasn't been studied in humans yet—that is to say, people who are doing genetic studies in humans haven't been looking at the combined effects with environmental risk factors. That may be part of the puzzle for why the effect sizes of most mutations are so small, because maybe the mutations have to occur in combination with an environmental risk factor.

Q: That makes sense to me.

A: That's point number one: the genetics of it. Point number two: it's frustrating that so much less attention is paid to environmental risk factors compared to genetic risk factors, because the effect size of maternal infection is so great. I think the epidemiology deserves a lot more attention than it has been getting.

Q: Do you think maternal infection could be related to some of the epidemiological factors that have been found to be related to schizophrenia, such as social density?

A: Yes, the point has been made that a number of other risk factors found by epidemiology, which are seemingly so disparate and unrelated, could in theory all be related to this maternal infection. That would include being born and raised in an urban environment and being born in winter-spring months, both of which would enhance the probability of maternal infection. Also, obstetric complications and maternal stress increase the risk for schizophrenia, and these involve increases in IL-6 levels, which the mouse studies showed to be critical for schizophrenia-like behaviors in the offspring.

Q: In addition, certain immigrant communities face a higher risk.

A: It's conceivable that when people are transplanted into a different environment, they could be more susceptible to infection by microbes they have not encountered before. Obviously, there are many other factors that are new to the immigrant as well, but it is interesting to think about unifying hypotheses.

Q: Thank you so much for taking the time to talk with me; I really appreciate it.

 
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