Abstract
Over recent years, it has been proposed that some diseases of unknown origin, such as schizophrenia, may be caused by persistent chronic infections coupled with a genetic component and may be perpetuated by the immune system. This hypothesis is supported by epidemiological and biological evidence on the exposure of schizophrenics to infectious diseases during prenatal or postnatal periods, including Toxoplasma gondii, chlamydia, human herpes virus, human endogenous retroviruses, parvovirus B19, mumps, and flu viruses. This growing list of microbes will undoubtedly continue to increase in the future. Linking infection to schizophrenia is a complex challenge that requires further experimental and epidemiological research. T. gondii is the infectious agent that has most frequently been related to neuropsychiatric disorders, including schizophrenia, and it is considered to represent a highly useful model to analyze the influence of a microorganism on human behavior and the development of psychiatric disease. It may also help to detect patient subpopulations susceptible to treatment with specific antimicrobials by improving definition of the differential phenotype of the disease, and it offers the possibility of a preventive approach.
Keywords
- schizophrenia
- Toxoplasma gondii
- antibodies
- behavior
- cytokine
- neurotransmitter
- gene‐infection interaction
1. Introduction
Over the past few years, it has been proposed by some authors that schizophrenia may be caused by central nervous system (CNS) disorders during neurodevelopment (i.e., congenital) or during the postnatal period, at least in some patient subgroups [1]. These disorders may be related to environmental exposure to toxic products, radiation, stress, fetal hypoxia, nutritional problems, infections (especially when chronic and persistent), and/or, according to more recent data, gut microbiota [2, 3]. Any of these exposures could possibly affect cognitive functions and behavior patterns with important neuropsychiatric consequences, including irreversible neurological lesions leading to neuronal dysfunction, behavior problems, mental retardation, learning difficulties, or mood disorders [4–9]. Participation by microbial agents in the development of schizophrenia is suggested by medical evidence, with prenatal or perinatal infection being the most frequent cause of severe congenital malformations and mental impairment [10]. Their involvement is also supported by epidemiological evidence on the exposure of schizophrenic patients to
According to current pathogenic models, microorganisms may produce various inflammatory and/or immunological disorders in the infected brain, giving rise to neurotransmitter synthesis disorders with important clinical repercussions [7]. Schizophrenia has been related to the production of inflammatory cytokines that alter the synthesis of dopamine and other neurotransmitters [12] and to fetal neuronal tissue damage due to the transplacental transfer of maternal antibodies, which might underlie development of the disease decades later [13]. This association with inflammatory and immunologic disorders has been observed in studies of animal models and human cells. Thus, maternal infection of mice and rats during pregnancy was associated with behavioral disorders in the offspring that were very similar to those reported in schizophrenic patients. Various studies in murine models revealed an association between prenatal infection and marked deficits in sensory information processing, in the expression of certain neurotransmitters (e.g., dopamine) and of cytokines, and in the immune function, all of which emerged in the offspring. Their onset is at an age equivalent to human adolescence and is earlier, with more severe effects, in male
There is intense and increasing research interest in the relationship between schizophrenia and infectious agents. Irreversible mild or severe neurophysiologic alterations may result from fetal infection, maternal infection with secondary fetal involvement
Primary infection usually takes place during childhood, when only a small percentage of people show symptoms, which are mild and include general discomfort, lethargy, cervical lymphadenopathy, and/or eye disease, among others. Most parasitized individuals remain asymptomatic for a long time period, even throughout their life, and host the latent form of
2. Epidemiologic data on the association between toxoplasmosis and schizophrenia
One of the first approaches adopted to explore a possible relationship between
Both have a familial incidence. This is explained in the case of schizophrenia by the possible participation of certain genes in its pathogeny [21], and in the case of toxoplasmosis by the possible common exposure of family members to the parasite, although a genetic influence has also been proposed [22].
There is a relatively high frequency of stillborns among both schizophrenic [23] and parasitized [24] mothers.
Both diseases typically show a decreased prevalence in geographic areas with small populations of felines [25, 26].
Initial symptoms in both diseases commonly manifest between the second and third decade of life [27, 28].
The prevalence of both diseases is higher among populations with lower socioeconomic level and living in overcrowded conditions [29, 30].
These and other published findings indicate that the two diseases have some similar features and may even be epidemiologically related. However, they are inadequate to establish etiological relationships, and a pathophysiological approach is required to explore causality.
3. Studies based on the detection of anti‐Toxoplasma gondii antibodies
For more than six decades, the relationship between schizophrenia and toxoplasmosis has been explored by studying a specific immune response [31]. Various meta‐analyses have demonstrated a significantly higher prevalence of anti‐
In the natural time course of toxoplasmosis, IgM antibodies against
Most studies have centered on the humoral immune response, comparing anti‐
Clinical manifestations differ between seropositive and seronegative schizophrenic patients, with a predominance in the former of positive symptoms (delirium, hallucinations, disorganized thinking), cognitive disorders (abstract thinking difficulties, disorientation, attention deficit), and agitation [50, 54]. Some researchers also observed that patients with schizophrenia and anti‐
The above studies suggest a strong association between these diseases, with a significantly higher frequency of chronic parasitization in schizophrenic patients than in other population groups. However, if schizophrenia is a consequence of chronic CNS infection, which usually takes place at an early age, the question arises as to why it typically appears between the second and third decades of life. According to Yolken et al. [51], a significant increase in IgG titers observed in patients with a first schizophrenia episode may be compatible with a reactivation of the infection (previously in latent phase) that becomes clinically manifest in the onset of the disease
However, although a strong association has been described between schizophrenia and parasitization, these studies do not provide evidence to confirm the hypothesis on the infectious etiology of schizophrenia, and a causal relationship has not been demonstrated. Contact with
4. Seroprevalence studies in mothers and newborns
The possible transplacental transmission of
This type of study can be classified into two groups: those on the presence of antibodies in pregnant women and the development of schizophrenia in their offspring; those on the presence of antibodies in newborns and their later development of schizophrenia. Among the former, Brown et al. [60] and Blomström et al. [61] demonstrated associations between increased anti‐
Published data suggest that schizophrenia risk in offspring is associated with persistent maternal infection by
As noted above, increased maternal IgG levels can cross the placenta (unlike IgM antibodies) and may damage fetal brain development by molecular mimicry [60, 64]. However, the presence of maternal IgG may indicate a reactivation of latent infection due to the impact of immune system disorders on protozoan replication control during pregnancy [66]; hence, brain development could also be impaired by transplacental transmission and/or the passage of inflammatory cytokines to the fetus [67, 68].
The majority of schizophrenic patients do not have anti‐
5. Studies based on Toxoplasma gondii nucleic acid detection
Studies of animal brain biopsies have shown
However, the presence of brain cysts can only be detected in
One of the few studies of
A study of blood samples detected parasite DNA in 33 out of 101 samples from schizophrenic patients
6. Studies on behavioral disorders in animals and humans
Research on this issue has included experimental animal studies, mainly in rats and mice. Parasitized animals have shown various behavioral changes, becoming more active, expressing less fear when examining new stimuli, reducing their natural aversion to cat odor or even becoming attracted to it, and demonstrating reduced learning ability and attention or memory deficits [78–83]. According to the “behavioral manipulation hypothesis,” these disorders in their intermediate hosts (rodents) represent an evolutionary adaptation of the parasite, facilitating their capture by their definitive host (felines) and completing their life cycle [84, 85]. Although the mechanism by which
Any of the above mechanisms in rodents could also produce behavioral changes in the brains of other intermediate hosts, including humans. Thus, research in humans also suggests that toxoplasmosis may alter behavior, psychomotor abilities, or personality, with the corresponding clinical consequences [84]. These disorders would be more related to latent rather than acute toxoplasmosis, given that its emergence, frequently several years after primary infection and not during the acute phase, would indicate that it results from slow and possibly accumulative changes induced by parasite activity [91–93]. The study by Horacek et al. [76] demonstrates that, in seropositive schizophrenic patients, latent parasitization is associated with a significant reduction in gray matter volume in specific brain areas (cortical regions, hippocampus, and caudate nucleus), which is not observed in seronegative patients.
Reinforcing the relationship between the parasite and the psychiatric disease, it has been demonstrated that haloperidol, an antipsychotic drug that blocks D2 dopaminergic receptors in the mesolimbic system and often used in the symptomatic treatment of schizophrenia, inhibits the replication of tachyzoites in cell cultures
Antipsychotics are especially indicated in patients with a predominance of positive symptoms and agitation (as in the acute phase of schizophrenia), which are significantly more frequent in those parasitized with
Studies to date on the possible effect in these patients of drugs with anti‐
The etiological relationship between parasitization and schizophrenia has not yet been established, despite the above data on behavioral changes in animals or humans and on the effects of antipsychotic drugs on symptoms. In addition, differences in behavioral disorders between humans and rodents may mean that results in animal models cannot be extrapolated to humans. It should also be borne in mind that the mild behavioral modifications associated with the infection cannot necessarily be considered symptoms of a psychotic disease.
7. The role of proinflammatory cytokines
The host response to the parasitization of glial cells and neurons involves the activation of immune system cells, including T lymphocytes (CD4+ and CD8+), B lymphocytes, NK cells, macrophages, and dendritic and glial cells. These produce a wide variety of inflammatory cytokines such as IFNγ, interleukins (IL‐1, IL‐1β, IL‐2, IL‐4, IL‐6, IL‐10, IL‐12, IL‐15, IL‐17, IL‐18, IL‐23), granulocyte macrophage colony‐stimulating factor (GM‐CSF), and/or TNFα [69, 103]. These cytokines halt protozoan proliferation and limit their replication, playing a key role in regulating the infection of host cells, thereby favoring the formation of tissue cysts and the development of the chronic latent form [20]. These and other inflammatory responses have also been reported in schizophrenia [104] and are therefore involved in brain disorders both in this disease and in
Thus, infection of brain tissue by
8. The importance of dopamine and other neurotransmitters
As already noted, some experimental animal and human studies concluded that behavioral changes may be explained by increased dopamine levels in the parasitized brain, and that these disorders could largely be resolved by administration of a dopaminergic receptor antagonist (e.g., haloperidol) or dopamine reuptake inhibitor (e.g., GBR‐12909) [96, 114, 115]. It is therefore possible that dopamine represents the link between toxoplasmosis and schizophrenia [97]. This neurotransmitter is synthesized in the cytosol of neurons from l‐tyrosine amino acid by the action of the tyrosine hydroxylase enzyme, which converts it to l‐3,4‐dihydroxyphenylalanine (l‐DOPA). l‐DOPA is in turn converted by the action of DOPA‐decarboxylase (DDC) to dopamine, a precursor of norepinephrine (noradrenalin) and epinephrine (adrenalin) in the synthesis pathway of these catecholamines. It is subsequently packaged in vesicles and transported through the axon to the synapse, where it is released by exocytosis in response to an electrical stimulus. Dopamine is one of the main neurotransmitters in the prefrontal cortex and the mesolimbic system (mainly formed by the nucleus accumbens, amygdala, and hippocampus), where the presence of
The definitive mechanism by which
Parasitization in the fetal period may also impair the development of mesolimbic dopaminergic or prefrontal cortex neurons (inappropriate migration, altered position, reduced synapses, etc.) leading to neurodevelopmental disorders. Disease symptoms would not be induced immediately by these early anomalies but would rather manifest after a latency period of one to three decades. This is because the proliferation, migration, differentiation, and maturation of glial progenitor cells continue throughout childhood [119] and the volume of gray matter increases to a peak in puberty before beginning to diminish [120].
However, the hypothesis that increased dopamine levels or dopaminergic hyperactivity is the underlying cause of schizophrenia does not account for the negative symptoms in these patients, which are more likely to result from dopaminergic hypoactivity. Therefore, neurotransmitters other than dopamine may play an important role in the development of this disease. Thus, it has been proposed that deficits in glutamatergic brain systems also participate in the physiopathology of schizophrenia based on findings of higher kynurenic acid levels in patients with psychotic symptoms than in healthy controls [121]. Kynurenic acid is a metabolite of tryptophan with important biological effects on the nervous system, related to its antagonism for the glutamate receptor in the human brain (it is a glutamatergic NMDA receptor antagonist). Increased kynurenic acid levels due to blockade of NMDA receptors in glutamatergic neurons have been related to changes in dopamine level in different brain areas. These modifications include cortical dopaminergic hypoactivity and mesolimbic dopaminergic hyperactivity, which would explain the negative and positive symptoms in patients. This relationship between glutamate pathway disorders and dopamine level changes may explain the presence of different symptoms in the psychosis [122].
Indoleamine‐2,3‐dioxygenase and therefore the metabolism of tryptophan, a precursor metabolite in serotonin (and melatonin) synthesis, are induced by the proinflammatory cytokines released in response to
Patients with schizophrenia also show anomalous levels of gamma‐aminobutyric acid (GABA), another important neurotransmitter [20], which is synthesized from glutamate by the action of glutamic acid decarboxylase (GAD) [127]. GABA activates GABAA receptors, which are ion channels, and GABAB receptors, which are G‐protein‐coupled receptors [128]. It is the main neurotransmitter with inhibiting effect in the CNS, regulating dopaminergic activity and playing a key role in the reduction of neuronal excitability throughout the nervous system. Dopaminergic neurons in basal ganglia would be directly inhibited by GABAergic neurons, so that any GABAergic hypofunction would be accompanied by an increase in subcortical dopaminergic activity, as observed in schizophrenia.
More direct evidence of the involvement of this neurotransmitter in the etiology of schizophrenia derives from data on the reduction in neurons in the GABAergic system or in brain regions such as the hippocampus, temporal lobe, and prefrontal cortex of schizophrenic patients [129–131].
Outside the nervous system, GABAergic mechanisms have been observed in different tissues and peripheral organs, and GABA has also been found to exert a major role in the immune system, with important inter‐regulatory functions between this and the CNS [136]. It has been reported that
Accordingly, the inflammatory response of the host to parasitization, which aims to control parasite replication and alterations in differentiation and migration processes, can change levels of dopamine, tryptophan, kynurenic acid, serotonin, and GABA, leading to behavioral changes and giving rise to different psychotic symptoms.
In order to establish dopamine and other related neurotransmitters as a causal link between toxoplasmosis and schizophrenia development, it is necessary to confirm that this neurotransmitter is also involved in the disease genesis when there is infection by other pathogens [140], and this mechanism should also explain the possible contribution of
9. The N ‐methyl‐d‐aspartate receptor hypofunction theory: anti‐NMDAr antibodies
Encephalitis due to antibodies against the glutamatergic NMDA receptor (anti‐NMDAr antibodies) is an autoimmune disease caused when antibodies produced by the host immune system identify NMDA receptors as foreign antigens. This receptor forms a heterotetramer between two GluN1 and two GluN2 subunits and participates in essential functions for reality perception, memory, and the control of unconscious activities. The disease is characterized by the hypofunction of NMDA receptors, which would account for the psychotic symptoms, personality changes, memory impairment, and psychomotor agitation [141, 142]. It usually arises during the course of a paraneoplastic process and is frequently associated with the development of ovarian teratomas, explaining its higher incidence among females [143, 144]. Likewise, 14–75% of patients with systemic erythematous lupus, another autoimmune disease, have been reported to manifest psychiatric symptoms related to the presence of the same antibodies [145, 146]. This involvement of anti‐NMDAr antibodies (and other neurotransmission receptors) indicates an important link between immune abnormalities and altered neurotransmission in schizophrenia, major depression, or bipolar disorder [147, 148].
The presence of anti‐NMDAr antibodies has been documented in schizophrenic patients in the absence of seizures, movement disorders, or other neurological signs or symptoms [149–151], although other researchers were unable to replicate these findings [152, 153]. For various reasons, the production of anti‐NMDAr antibodies is a plausible mechanism to explain at least a percentage of schizophrenic cases [149]: several studies reported that 5–10% of cases are associated with the presence of these antibodies in serum and cerebrospinal fluid [150, 151, 154]; kynurenic acid is an antagonist of glutamate
Maternal infection during brain development or infection during childhood may produce anti‐NMDAr antibodies, while other environmental or genetic factors may influence the age of disease onset [149]. Certain pathogens have been associated with elevated anti‐NMDAr antibodies [162, 163]. Thus, a
10. Studies on gene‐infection interaction
Various studies have demonstrated the participation of numerous genes in schizophrenia, providing firm evidence on the involvement of genetics in the etiology of the disease [165]. Some authors have described inheritability in >80% of cases, and schizophrenia has been associated with polymorphic variability in certain genes [21, 166–168]. However, the genetic hypothesis alone cannot explain the familial association of schizophrenia with other diseases, the seasonal peaks of schizophrenia births, the different prevalences among residents of urban and rural areas, discordant results between monozygotic and dizygotic twins or between dizygotic twins and full siblings, or correlations in adopted children, which are, however, consistent with an infectious etiology [1]. Schizophrenia is likely a genetically complex disease that does not follow a Mendelian transmission pattern but rather involves multiple genes, each with a small effect, which act in combination with epigenetic and environmental factors [169]. Accordingly, epidemiological findings suggest that a combination of intrinsic (genetic) and extrinsic or environmental factors, including infections, may participate in the origin of this disease, operating during the development of the individual at some time between conception and adolescence [7]. Tomonaga [170] proposed that persistent chronic infections or the expression of microbial proteins may directly and/or indirectly affect CNS functions in infected individuals, changing the expressions of genes related to schizophrenia and increasing the risk of suffering this disease or at least some of its varied clinical phenotypes.
Genes whose variants or polymorphisms have been associated with the risk of schizophrenia include some that encode proteins with important functions in neurodevelopment or neurodegeneration and in neuronal neurotransmission circuits. This is the case of the gene that encodes neuregulin 1 (NRG1), a key molecule in maintaining brain synaptic plasticity in adults, which has been related to schizophrenia etiology [171, 172], and the genes that encode catechol‐O‐methyltransferase (COMT) [173], proline dehydrogenase (PRODH) [174], dysbindin protein (DTNBP1) [175], a regulator of G4 protein (RGS4) [176], a regulator of potassium calcium channels (KCNN3) [177], and d‐amino‐oxidase complex (G72, DAAO) [178], among others [179]. The genes that encode these proteins are located in chromosomal regions that have been described as relevant for the study of schizophrenia, and many of these proteins participate in glutamatergic, dopaminergic, or serotonergic neurotransmission circuits.
Genetic polymorphisms that increase susceptibility to schizophrenia, including some of the above, have also been related to resistance or susceptibility to certain infections through their important role in the life cycle of some pathogens, including
Various rodent [79, 183, 184] and human [185, 186] studies have supported the existence of genetic susceptibility to
Genetic studies (in animals and humans) currently center on the possible presence of genes or specific allelic variants that interact with the genes of microorganisms that can infect the patient (gene‐infection interaction hypothesis), increasing the risk of schizophrenia [187–189]. Thus, it has been demonstrated that a critical role in human congenital
A further example in support of this hypothesis is the Akt cell signaling system. The
Other researchers reported similar associations between schizophrenia risk and other human pathogens, supporting the gene‐infection interaction hypothesis [198–201]. This research line on the effects of interaction between genes or genetic variants on the risk of schizophrenia related to
11. Is there an etiological association between Toxoplasma gondii infection and schizophrenia development?
Numerous studies have contributed evidence on the involvement of toxoplasmosis in the pathogenesis of numerous CNS diseases, including bipolar disorder, depression, Alzheimer's disease, Parkinson's disease, and epilepsy [49, 202–204]. However, the main advances over the past few years have been achieved by research on deciphering the molecular mechanisms underlying the physiopathology of schizophrenia.
This chapter analyzes data from
Schizophrenia is a complex disease with innumerable symptoms, and its presentation and severity vary among patients. According to the infectious hypothesis of this disease (Figure 1), differences among patients would be influenced by their genetic predisposition or vulnerability, their immune status, the timing of parasitization (congenital, neonatal, or adult), the time interval since their first contact, and/or the particular brain area(s) affected. Characteristics of the infection also play a role, including its source (oocysts or tissue cysts), possible interactions with other infectious agents, and the genotype; thus, genotypes II and III more frequently establish chronic infections and show a greater expression of tyrosine hydroxylase genes in comparison with genotype I, and they may be more strongly related to behavioral changes [205].
Finally, the biology of schizophrenia must be fully elucidated to support the appropriate design of disease‐modifying therapies or novel antipsychotic drugs. There appears to be sufficient evidence to suggest that schizophrenic patients with
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