Over the past six years, Alan Brown and colleagues have published an impressive series of epidemiological findings on schizophrenia in the offspring of a large cohort of carefully studied pregnant women (reviewed by Brown, 2006). Their work has confirmed and greatly extended prior findings linking maternal infection in the second trimester with increased risk for schizophrenia in the offspring. Moreover, Brown et al. found an association between anti-influenza antibodies in maternal serum and increased risk for schizophrenia, as well as a similar association with elevated levels of a cytokine in maternal serum. In a new paper (Babulas et al., 2006), this group reports a fivefold increase in risk for schizophrenia spectrum disorders in the offspring of women who experienced a genital/reproductive infection during the periconception period. The infections considered were endometritis, cervicitis, pelvic inflammatory...  Read more

Over the past six years, Alan Brown and colleagues have published an impressive series of epidemiological findings on schizophrenia in the offspring of a large cohort of carefully studied pregnant women (reviewed by Brown, 2006). Their work has confirmed and greatly extended prior findings linking maternal infection in the second trimester with increased risk for schizophrenia in the offspring. Moreover, Brown et al. found an association between anti-influenza antibodies in maternal serum and increased risk for schizophrenia, as well as a similar association with elevated levels of a cytokine in maternal serum. In a new paper (Babulas et al., 2006), this group reports a fivefold increase in risk for schizophrenia spectrum disorders in the offspring of women who experienced a genital/reproductive infection during the periconception period. The infections considered were endometritis, cervicitis, pelvic inflammatory disease, vaginitis, syphilis, condylomata, “venereal disease,” and gonorrhea. Strengths of the study include physician documentation of the infections and face-to-face assessments of schizophrenia. Although sample size was modest, these results extend a prior finding that elevated maternal anti-herpes simplex type 2 antibodies are associated with increased risk of psychotic disorders, including schizophrenia (Buka et al., 2001).

The mechanism of how maternal infection increases risk for schizophrenia could involve pathogens invading the fetus. Although this is certainly possible in the case of some of the infections studied by Babulas et al., in the case of a respiratory virus such as influenza, this explanation appears unlikely. A more parsimonious mechanism would involve activation of the maternal immune system, and action of soluble mediators such as cytokines at the level of the placenta or the fetus. Support for this hypothesis comes from animal studies. An antiviral immune response can be evoked in the absence of the pathogen by injection of synthetic double-stranded RNA (polyI:C). When this is done in pregnant rats or mice, the adult offspring display a number of behavioral abnormalities reminiscent of those observed in schizophrenia. These include deficits in prepulse inhibition, latent inhibition, and social interaction, as well as enhanced amphetamine-induced locomotion and anxiety under mildly stressful conditions (Shi et al., 2003; Zuckerman et al., 2003; Ozawa et al., 2005). Moreover, some of these deficits are ameliorated by treatment with antipsychotic drugs and exacerbated by psychotomimetics (Shi et al., 2003; Ozawa et al., 2005), and the offspring also exhibit dopaminergic hyperfunction (Zuckerman et al., 2003; Ozawa et al., 2005). Some of these abnormalities are also seen in the offspring of influenza-infected mothers or mothers injected with the bacterial cell wall component, LPS (Borrell et al., 2002; Fatemi et al., 2002; Shi et al., 2003).

The most recent advance in this growing cottage industry is the finding that there are critical periods of maternal immune activation that determine the type of adult behavioral dysfunction and neuropathology found in the offspring (Meyer et al., 2006). Injection of polyI:C during stages of mouse gestation corresponding to first-to-second versus second-to-third trimesters of human pregnancy yields different deficits in exploratory and perseverative behavior, postnatal reelin expression, and hippocampal apoptosis. Moreover, these two different stages of injection evoke diverse cytokine responses in the fetal brain. It would further be interesting to know which of these abnormalities is specific to the period corresponding to the human second trimester, as this is the key time of vulnerability for risk of schizophrenia associated with maternal infection.

Other fascinating questions for this increasingly popular model are, what mediates the effects of maternal immune activation (e.g., cytokines, antibodies, corticosteroids), and do they act directly on the fetus or via the placenta? Can imaging be used with the rodents to explore dopamine receptor occupancy? Which of the observed pathologies are most relevant for each of the behavioral abnormalities?

References:
Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS. Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry. 2006 May;163(5):927-9. Abstract Borrell J, Vela JM, Arevalo-Martin A, Molina-Holgado E, Guaza C. Prenatal immune challenge disrupts sensorimotor gating in adult rats. Implications for the etiopathogenesis of schizophrenia. Neuropsychopharmacology. 2002 Feb;26(2):204-15. Abstract Brown AS. Prenatal infection as a risk factor for schizophrenia. Schizophr Bull. 2006 Apr;32(2):200-2. Epub 2006 Feb 9. Abstract Buka SL, Tsuang MT, Torrey EF, Klebanoff MA, Bernstein D, Yolken RH. Maternal infections and subsequent psychosis among offspring. Arch Gen Psychiatry. 2001 Nov;58(11):1032-7. Abstract Fatemi SH, Earle J, Kanodia R, Kist D, Emamian ES, Patterson PH, Shi L, Sidwell R. Prenatal viral infection leads to pyramidal cell atrophy and macrocephaly in adulthood: implications for genesis of autism and schizophrenia. Cell Mol Neurobiol. 2002 Feb;22(1):25-33. Abstract Meyer U, Feldon J, Schedlowski M, Yee BK. Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia. Neurosci Biobehav Rev. 2005;29(6):913-47. Abstract Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci. 2006 May 3;26(18):4752-62. Abstract Ozawa K, Hashimoto K, Kishimoto T, Shimizu E, Ishikura H, Iyo M. Immune activation during pregnancy in mice leads to dopaminergic hyperfunction and cognitive impairment in the offspring: a neurodevelopmental animal model of schizophrenia. Biol Psychiatry. 2006 Mar 15;59(6):546-54. Epub 2005 Oct 26. Abstract Shi L, Fatemi SH, Sidwell RW, Patterson PH. Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci. 2003 Jan 1;23(1):297-302. Abstract Zuckerman L, Rehavi M, Nachman R, Weiner I. 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. 2003 Oct;28(10):1778-89. Abstract

Meyer and coworkers provide interesting new data on the role of the immune system in mediating the damage caused by viral infections during pregnancy on the developing nervous system of the fetus. Not just the timing of the infection appears to be critical, but the developing fetal immune system appears to play a role, too.

Polyinosinic-polycytidylic acid (polyI:C), which was employed by Meyer et al., is frequently used to mimic viral infections. It is a synthetic double-stranded RNA and has adjuvant-effects (Salem et al., 2005). PolyI:C binds to target cells via the "Toll-like receptor 3" (TLR3). TLR3 serves as a receptor in trophoblast cells and uterine epithelial cells mediating local immune activation at the maternal-fetal interface after viral infections (Abrahams et al., 2005; Schaefer et al., 2005). Glial cells like microglia and...  Read more

Meyer and coworkers provide interesting new data on the role of the immune system in mediating the damage caused by viral infections during pregnancy on the developing nervous system of the fetus. Not just the timing of the infection appears to be critical, but the developing fetal immune system appears to play a role, too.

Polyinosinic-polycytidylic acid (polyI:C), which was employed by Meyer et al., is frequently used to mimic viral infections. It is a synthetic double-stranded RNA and has adjuvant-effects (Salem et al., 2005). PolyI:C binds to target cells via the "Toll-like receptor 3" (TLR3). TLR3 serves as a receptor in trophoblast cells and uterine epithelial cells mediating local immune activation at the maternal-fetal interface after viral infections (Abrahams et al., 2005; Schaefer et al., 2005). Glial cells like microglia and astrocytes also express functional TLR3 (Farina et al., 2005; Park et al., 2006; Town et al., 2006). Thus, TLR3 plays an important role in immune responses, and its natural function appears to be immune activation in addition to cross-priming the immune system to virus-infected cells (Schulz et al., 2005). Given the expression of TLR3 at the maternal-fetal interface and on glial cells, the polyI:C-TLR3-model appears to be useful to study the basic mechanisms of viral infections and their consequences for brain development in animal models.

However, several limitations are evident: PolyI:C is not a virus, and different immunological pathways may be activated by intact viruses after binding to their appropriate receptors. Findings from the immune system of rodents cannot be directly transferred to humans, and it may be difficult to dissect—on a molecular level—the protective aspects of an immune response against a viral infection from its putative detrimental effects on human neurodevelopment. Still, such mechanisms may now be studied in the rodent models used by Meyer and coworkers and other groups, and this will help to pave the way for future studies in humans. This will hopefully lead to a better understanding of the role of the immune system and viral infections in the pathogenesis of schizophrenia.

References:

Abrahams VM, Visintin I, Aldo PB, Guller S, Romero R, Mor G. A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. J Immunol. 2005 Dec 15;175(12):8096-104. Abstract

Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F, Meinl E. Preferential expression and function of Toll-like receptor 3 in human astrocytes. J Neuroimmunol. 2005 Feb;159(1-2):12-9. Epub 2004 Nov 11. Abstract

Park C, Lee S, Cho IH, Lee HK, Kim D, Choi SY, Oh SB, Park K, Kim JS, Lee SJ. TLR3-mediated signal induces proinflammatory cytokine and chemokine gene expression in astrocytes: differential signaling mechanisms of TLR3-induced IP-10 and IL-8 gene expression. Glia. 2006 Feb;53(3):248-56. Abstract

Salem ML, Kadima AN, Cole DJ, Gillanders WE. Defining the antigen-specific T-cell response to vaccination and poly(I:C)/TLR3 signaling: evidence of enhanced primary and memory CD8 T-cell responses and antitumor immunity. J Immunother. 2005 May-Jun;28(3):220-8. Abstract

Schaefer TM, Fahey JV, Wright JA, Wira CR. Innate immunity in the human female reproductive tract: antiviral response of uterine epithelial cells to the TLR3 agonist poly(I:C). J Immunol. 2005 Jan 15;174(2):992-1002. Abstract

Schulz O, Diebold SS, Chen M, Naslund TI, Nolte MA, Alexopoulou L, Azuma YT, Flavell RA, Liljestrom P, Reis e Sousa C. Toll-like receptor 3 promotes cross-priming to virus-infected cells. Nature. 2005 Feb 24;433(7028):887-92. Epub 2005 Feb 13. Abstract

Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA. Microglia recognize double-stranded RNA via TLR3. J Immunol. 2006 Mar 15;176(6):3804-12. Abstract

The research being carried out by Dr. Sapolsky and colleagues at Stanford is potentially very important for understanding schizophrenia. (In regard to full disclosure, it should be noted that the Stanley Medical Research Institute (SMRI) is funding Dr. Sapolsky’s research as well as other research on dopamine and Toxoplasma gondii.)

The origin of interest in dopamine and T. gondii appears to have been the 1985 paper by Henry H. Stibbs, then in the School of Public Health and Community Medicine at the University of Washington. Stibbs had been studying trypanosomes and sleeping sickness for 10 years and discovered that this organism increased dopamine levels by 34 percent in infected rats (Stibbs, 1984). He therefore turned his attention to T. gondii because of its known ability to alter learning, memory, and behavior in infected mice and rats. He infected 30 mice with the C56 strain of T. gondii. Ten mice were infected, became symptomatic, and were killed at 12 days (= acute group). Ten mice were...  Read more

The research being carried out by Dr. Sapolsky and colleagues at Stanford is potentially very important for understanding schizophrenia. (In regard to full disclosure, it should be noted that the Stanley Medical Research Institute (SMRI) is funding Dr. Sapolsky’s research as well as other research on dopamine and Toxoplasma gondii.)

The origin of interest in dopamine and T. gondii appears to have been the 1985 paper by Henry H. Stibbs, then in the School of Public Health and Community Medicine at the University of Washington. Stibbs had been studying trypanosomes and sleeping sickness for 10 years and discovered that this organism increased dopamine levels by 34 percent in infected rats (Stibbs, 1984). He therefore turned his attention to T. gondii because of its known ability to alter learning, memory, and behavior in infected mice and rats. He infected 30 mice with the C56 strain of T. gondii. Ten mice were infected, became symptomatic, and were killed at 12 days (= acute group). Ten mice were infected, treated with sulfadiazine, did not develop symptoms, and were killed at five weeks (= chronic group). Ten control mice were also killed at five weeks. The brains were assessed neurochemically and compared to the controls. There were no changes in serotonin or 5-HIAA. Norepinephrine was 28 percent decreased in acute but not in chronic infection. Homovanillic acid (HVA) was 40 percent increased in acute but not chronic infection. Dopamine was normal in acute infection but 14 percent increased in the treated mice with chronic infection. Stibbs concluded that T. gondii causes abnormalities in catecholamine metabolism and that these “may be factors contributing to the psychological and motor changes” seen in experimentally infected rodents (Stibbs, 1985).

Joanne Webster and her colleagues at Oxford infected rats with T. gondii, then treated them with haloperidol, an antipsychotic known to block dopamine. The effect of the haloperidol was to reverse the behavioral effects of T. gondii. They speculated that possible explanatory mechanisms include the ability of haloperidol “to inhibit T. gondii replication and to reduce, directly and indirectly, dopamine levels” (Webster et al., 2006).

Jaroslav Flegr and his colleagues in Prague have studied the effects of T. gondii infection on the behavior of mice. They reported that giving the mice a dopamine reuptake inhibitor (GBR 12909) altered the behavior of the mice and concluded that “the proximal causes of alterations in mice behavior induced by Toxoplasma gondii are probably changes in the dopaminergic system” (Skallová et al., 2006). In other publications, Flegr and colleagues have speculated that dopamine is the “missing link between schizophrenia and toxoplasmosis,” specifically suggesting that dopamine is increased by activated cytokines (e.g., IL–2) as a consequence of infection (Flegr et al., 2003; Flegr, 2007).

The intriguing thing about this research is its possible relevance to schizophrenia. For more than 40 years, it has been clear that an excess of dopamine is somehow involved in the pathogenesis of schizophrenia. Despite hundreds of studies, however, relatively few abnormalities have been identified in the dopamine production of individuals with schizophrenia. If T. gondii is part of the disease’s etiology, the excess dopamine may be being introduced exogenously by the parasite. If true, this would introduce a whole new approach to treatment.

An important aspect of this body of work is that it provides an evolutionary basis for why an infectious agent might lead to altered behavior. In terms of Toxoplasma, this association is based on the organism’s life cycle. The primary host for Toxoplasma is the cat. Toxoplasma organisms can complete their replication cycle, including their sexual stage, within members of the feline species. If other animals become infected, the organisms can undergo some replication but cannot complete the sexual stage. The Toxoplasma organism must thus do something in order to get back into the cat if it is to complete its life cycle. Since the organism cannot get around on its own, it has to alter the behavior of its host if it is to accomplish this vital evolutionary goal. Dr. Sapolsky and others have documented the behavioral alterations associated with Toxoplasma infection. If the host is a rodent, the end result of these alterations is that the rodent gets eaten and the Toxoplasma is quite happy (even if the rodent is obviously not). This may also have been the case for prehistoric humans, who were also the frequent prey of large cats. While getting eaten by cats is not a problem for most modern humans, the Toxoplasma organism does not know this and still attempts to alter the behavior of its host. The vestigial effect of Toxoplasma infection may thus result in the altered behaviors that are the hallmark of schizophrenia, bipolar disorder, and other psychiatric disorders.

A summary of current research on T. gondii and schizophrenia can be found on the SMRI website (Laboratory of Developmental Neurovirology, Toxoplasmosis–Schizophrenia Research).

References:

Stibbs HH, Neurochemical and activity changes in rats infected with Trypanosoma brucei gambiense, J Parasitology 1984;70:428–432. Abstract

Stibbs HH, Changes in brain concentrations of catecholamines and indoleamines in Toxoplasma gondii infected mice, Ann Trop Med Parasitol 1985;79:153–157. Abstract

Webster JP, Lamberton PH, Donnelly CA, Torrey EF. Parasites as causative agents of human affective disorders? The impact of anti-psychotic, mood-stabilizer and anti-parasite medication on Toxoplasma gondii's ability to alter host behaviour. Proc Biol Sci. 2006 Apr 22;273(1589):1023-30. Abstract

Skallová A, Kodym P, Frynta D, Flegr J. The role of dopamine in Toxoplasma-induced behavioural alterations in mice: an ethological and ethopharmacological study. Parasitology. 2006 Nov 1;133(Pt 5):525-35. Abstract

Flegr J, Preiss M, Klose J, Havlícek J, Vitáková M, Kodym P. Decreased level of psychobiological factor novelty seeking and lower intelligence in men latently infected with the protozoan parasite Toxoplasma gondii Dopamine, a missing link between schizophrenia and toxoplasmosis? Biol Psychol. 2003 Jul 1;63(3):253-68. Abstract

Flegr J, Effects of Toxoplasma on human behavior, Schizophr Bull 2007;33:757-760. Abstract

Congratulations to Profs. Sapolsky, Torrey, and Yolken for their important contribution to this field. The question for me is rather an evolutionary one: is there any trace in the neuron-immuno-endocrine system of patients with schizophrenia that can reflect the adaptation to this hijacking attempt of this protozoon? Recent meta-analyses have provided a comprehensive overview of studies investigating Toxoplasma gondii antibodies in schizophrenic patients, thus attempting to clarify the potential role these infections might play in causing schizophrenia (Torrey and Yolken, 2007). Associations and theories that may enrich the current level of knowledge with regard to this significant subject deserve attention. Anti-parasitic agents as well as antipsychotics are effective in treating parasitosis. Both classes of drugs have been shown to exert dopaminergic activity. Parasites and human organisms have a long history of mutual contact. The effect of parasitosis on the host and the host's response to infection are undoubtedly the...  Read more

Congratulations to Profs. Sapolsky, Torrey, and Yolken for their important contribution to this field. The question for me is rather an evolutionary one: is there any trace in the neuron-immuno-endocrine system of patients with schizophrenia that can reflect the adaptation to this hijacking attempt of this protozoon? Recent meta-analyses have provided a comprehensive overview of studies investigating Toxoplasma gondii antibodies in schizophrenic patients, thus attempting to clarify the potential role these infections might play in causing schizophrenia (Torrey and Yolken, 2007). Associations and theories that may enrich the current level of knowledge with regard to this significant subject deserve attention. Anti-parasitic agents as well as antipsychotics are effective in treating parasitosis. Both classes of drugs have been shown to exert dopaminergic activity. Parasites and human organisms have a long history of mutual contact. The effect of parasitosis on the host and the host's response to infection are undoubtedly the product of a long evolutionary process. The neurochemical background of delusions of parasitosis is potentially similar to ancient evolutionary traces of altered neurotransmission and neuropeptide gene expression caused by parasites; these include fungal and viral infections. This is very unique in medicine if a class of drugs is effective in the treatment of an illness but also cures the delusion of the same disorder as well. Furthermore, metabolic disturbances such as hyperglycemia and insulin resistance were reported several decades before the antipsychotic era. Toxoplasmosis may also be linked to insulin resistance.

Although it would be important to established treatment trials, specifically by demonstrating that medications suppressing T. gondii infections improve the clinical symptoms of schizophrenia, it is not clear whether this would be a direct link. This experiment would be similar to the observations made in children affected by the PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) syndrome. The term is used to describe children who are believed to have developed obsessive-compulsive disorder (OCD) and/or tic disorders such as the Tourette syndrome following a group-Aβ-hemolytic streptococcal infection. However, studies with PANDAS children have shown that antibiotic treatment is not consistently effective in reducing the infection rate or the severity of obsessive-compulsive and/or tic symptoms in these children. Once the damage has occurred, corrective treatment against the infective agent is not always beneficial.

Schizophrenia research can benefit from understanding this evolutionary link. New chemical entities that are liable to alter neurochemical changes related to the brain's perception of the risk of predation secondary to parasites may result in new approaches for the treatment of psychosis. Neuroendocrine changes in the brain and body of people with schizophrenia are probably ancient traces of survival strategy on these individuals. These findings suggest that further research is needed to clarify this evolutionary link between parasite infection and delusions of parasitosis. I believe this model may well open up new avenues of research in the discovery of drugs to counteract schizophrenia and related disorders (Treuer and Karagianis, 2006; Treuer et al., 2007; Treuer et al., 2008).

References:

Torrey Ef, Yolken RH. Schizophrenia and Toxoplasmosis. Schizophrenia Bulletin. 2007;33:727-728. Abstract

Treuer T, Martenyi F, Karagianis J: Parasitosis, Dopaminergic Modulation and Metabolic Disturbances in Schizophrenia: Evolution of a Hypothesis. NeuroEndocrinology Letters. 2007 Oct;28(5):535-40. Abstract

Treuer T, Karagianis J: Is Hunger a Driver of Cognitive Development? Neuropsychopharmacology. Oct 2006;(31)10:2326-2327. Abstract

Treuer T, Karagianis J, Hoffmann VP: Can Increased Food Intake Improve Psychosis? A Brief Review and Hypothesis. Current Molecular Pharmacology. 2008 November;1(3):270-272.

Treuer T: The Potential Role of Ghrelin in the Mechanism of Sleep Deprivation Therapy for Depression. Sleep Medicine Reviews. 2007 Dec;11(6):523-4.

The results of the research performed by Dr. Sapolsky and colleagues at Stanford, elaborating the results obtained by Drs. Berdoy and Webster at Oxford (Berdoy et al., 2000), are really fascinating. It should not be forgotten, however, that dopamine is not the only suspected molecule. There are several indirect and recently even direct indications for changed levels of testosterone in subjects with latent toxoplasmosis (Flegr et al., 2008). Moreover, the increased levels of dopamine in Toxoplasma infected mice and men seem to be byproducts of local brain inflammations, rather than a product of biologically important manipulation of the host behavior by the parasite. The results from human cytomegalovirus, i.e., the parasite transmitted by direct contact, not by predation, suggest that an infection of brain tissue by various parasites could increase the level of brain dopamine (Skallová et al., 2005). From the point of view of...  Read more

The results of the research performed by Dr. Sapolsky and colleagues at Stanford, elaborating the results obtained by Drs. Berdoy and Webster at Oxford (Berdoy et al., 2000), are really fascinating. It should not be forgotten, however, that dopamine is not the only suspected molecule. There are several indirect and recently even direct indications for changed levels of testosterone in subjects with latent toxoplasmosis (Flegr et al., 2008). Moreover, the increased levels of dopamine in Toxoplasma infected mice and men seem to be byproducts of local brain inflammations, rather than a product of biologically important manipulation of the host behavior by the parasite. The results from human cytomegalovirus, i.e., the parasite transmitted by direct contact, not by predation, suggest that an infection of brain tissue by various parasites could increase the level of brain dopamine (Skallová et al., 2005). From the point of view of schizophrenia research or even clinical practice, the question of whether the increased level of dopamine is a product of manipulation or a byproduct of brain infection, is, of course, not so important.

Recently, results of several large independent studies suggest that RHD positive subjects, especially heterozygotes, are protected against latent toxoplasmosis-induced impairment of reaction times (Novotná et al., 2008; Flegr et al., 2008). The RhD protein, which is the RHD gene product and a major component of the Rh blood group system, carries the strongest blood group immunogen, the D-antigen. The structure homology data suggest that the RhD protein acts as an ion pump of uncertain specificity and unknown physiological role. The protein is present mainly on the surface of erythrocytes; however, expression library data suggest that the RHD gene is expressed also in brain tissue. It seems to me that possible association between RhD phenotype and schizophrenia should be studied in the future.

References:

Berdoy M, Webster JP, Macdonald DW. Fatal attraction in rats infected with Toxoplasma gondii. Proc Biol Sci. 2000 Aug 7;267(1452):1591-4. Abstract

Flegr J, Lindová J, Kodym P. Sex-dependent toxoplasmosis-associated differences in testosterone concentration in humans. Parasitology. 2008 Apr 1;135(4):427-31. Abstract

Skallová A, Novotná M, Kolbeková P, Gasová Z, Veselý V, Sechovská M, Flegr J. Decreased level of novelty seeking in blood donors infected with Toxoplasma. Neuro Endocrinol Lett. 2005 Oct 1;26(5):480-6. Abstract

Novotná M, Havlícek J, Smith AP, Kolbeková P, Skallová A, Klose J, Gasová Z, Písacka M, Sechovská M, Flegr J. Toxoplasma and reaction time: role of toxoplasmosis in the origin, preservation and geographical distribution of Rh blood group polymorphism. Parasitology. 2008 Sep 1;135(11):1253-61. Abstract

Flegr J, Novotná M, Lindová J, Havlícek J. Neurophysiological effect of the Rh factor. Protective role of the RhD molecule against Toxoplasma-induced impairment of reaction times in women. Neuro Endocrinol Lett. 2008 Aug 1;29(4):475-81. Abstract

Drs. Sapolsky's and Vyas's recent body of data have provided significant mechanistic insights into the parasite manipulation hypothesis, the dopamine hypothesis of schizophrenia and the gene-environment etiological paradigm.

Since most of the human epidemiological data currently emphasizes Toxoplasma exposure from the prenatal period, do we know whether maternal infection results in dopamine alteration in the prenatal, neonatal or postnatal amydala? Is the effect caused directly by transplacental migration of the parasite to the prenatal amydala, or indirectly by maternal cytokine effects, such as IL6 or IL8, on the embryonic brain?

View all comments by Huan Ngo

It seems like both bacteria and protozoa have been shown to either increase or decrease certain defensin levels in humans (Sperandio et al., 2008; Wiesenfeld et al., 2002). Then there's a single report from Sabine Bahn's group of increased α-defensins in schizophrenia (Craddock et al., 2008). It is interesting to speculate whether Toxoplasma gondii might contribute to the change in defensin levels.

References:

Sperandio B, Regnault B, Guo J, Zhang Z, Stanley SL, Sansonetti PJ, Pédron T. Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression. J Exp Med. 2008 May 12;205(5):1121-32. Abstract

Craddock RM, Huang JT, Jackson E, Harris N, Torrey EF, Herberth M, Bahn S. Increased alpha-defensins as a blood marker for schizophrenia susceptibility. Mol Cell Proteomics. 2008 Jul 1;7(7):1204-13. Abstract

Wiesenfeld HC, Heine RP, Krohn MA, Hillier SL, Amortegui AA, Nicolazzo M, Sweet RL. Association between elevated neutrophil defensin levels and endometritis. J Infect Dis. 2002 Sep 15;186(6):792-7. Abstract

View all comments by Artyom Tikhomirov