Infection Via Protozoa And Other Inflammatory Agents
Infectious agents other than viral and bacterial organisms can induce inflammation during pregnancy and cause placental changes in pregnant animals and brain abnormalities in the exposed offspring. T. gondii infection in pregnant mice has been associated with increased expression of multiple chemokines, which were shown to be dependent upon IFN-Î³ expression .
Other non-organismal agents have been demonstrated to elicit the inflammatory response. Mercury has recently been shown to induce inflammatory markers such as vascular endothelial growth factor and IL-6 to be released by human mast cells . In light of these findings, Kempuraj et al. have suggested that mercury may have the potential to disrupt the blood brain barrier, thereby inducing brain inflammation. In pregnant women, even low-level mercury exposure has recently been associated with reduced cerebellar size in newborns .While there was no significant difference in the width, the length of the cerebellum was significantly smaller in offspring of mothers whose hair mercury levels were greater than 1 Î¼g/g .
Inflammation-induced hypoferremia, a common physiological response to all infections whereby cytokine activation reduces serum levels of non-heme iron, has also been shown to elicit long-lasting behavioral and dopamine changes in the offspring . Thus, it becomes clear that many factors can activate inflammatory pathways and cause brain abnormalities .
Integrating Viral And Neurodevelopmental Mechanisms: The Role Of Animal Models
Considering the dearth of knowledge as to how viruses can cause latent psychosis or pathology resembling schizophrenia, a variety of viruses with the ability to infect the developing brain could hold clues to the mechanisms of schizophrenia pathogenesis. Examples from studies focusing on LCMV in rats serve to illustrate the utility of animal models in addressing some of the controversies mentioned above including neuronal specificity, neurotransmitter alterations and mechanism of disease progression. In these studies we have focused on the hippocampal formation because its development is completed late in gestation, allowing for a subtle defect, and the adult hippocampus is functionally well poised to mediate schizophrenia symptoms because it is pivotal to memory gating and sensory representations, and is interconnected with other brain regions associated with schizophrenia., Moreover, reduced hippocampal volume and lateral ventricular enlargement are among the most consistent neuroanatomical findings in the disease.,
Causes: Nature Vs Nurture
Schizophrenia is a serious neuropsychiatric disorder of uncertain causes.As well as genetic factors, environmental exposures have been identified as increasing risk for the disease. Environmental factors associated with increased risk of schizophrenia include:
Perinatal and postnatal infections.1,2,3,4,
Additionally, the potential role of infections in the cause and development of schizophrenia is supported by the associations between schizophrenia risk and genes which control the bodys defence and immune response to infectious agents.5,6
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Schizophrenia And Inflammatory Markers
Schizophrenia is often accompanied by systemic inflammation and cell-mediated immune activation as shown by increased levels of cytokines, interleukin 2 receptors , interleukin 1 receptor agonist , acute phase reactants such as IL-1Î², IL-6, and transforming growth factor -Î² in plasma of subjects with schizophrenia . Cytokines may be divided into various categories based on their role in inflammation and their derivation. Pro-inflammatory cytokines, such as interleukin -1Î², IL-6, and tumor necrosis factor -Î±, are synthesized upon activation of the innate immune system and are responsible for febrile reactions, activation of phagocytes, vascular permeability, and release of inflammatory mediators, all of which are essential to the inflammatory response . Many anti-inflammatory cytokines, such as IL-10 and TGF-Î²1, act to inhibit pro-inflammatory cytokine production, and these two factors in particular have been shown to exert an anti-hypoxic effect .
Virus And Genes Involved In Causation Of Schizophrenia
- Aarhus University
- For the first time, researchers have found that a combination of a particular virus in the mother and a specific gene variant in the child increases the risk of the child developing schizophrenia.
Viruses and genes interact in a way that may increase the risk of developing schizophrenia significantly. This happens already in the developing fetus.
An international team of scientists led by Aarhus University, Denmark, has made this discovery. As the first in the world, they scanned the entire genome of hundreds of sick and healthy people to see if there is an interaction between genes and a very common virus — cytomegalovirus — and to see whether the interaction influences the risk of developing schizophrenia.
And it does.
Women that have been infected by the virus — and around 70 % has — will have a statistically significant increased risk of giving birth to a child who later develops schizophrenia if the child also has the aforementioned gene variant. This variant is found in 15 percent. The risk is five times higher than usual, the researchers report in Molecular Psychiatry.
No cause for alarm
But as schizophrenia affects 1 per cent of the global population, this new knowledge is very important.
“In the longer term, the development of an effective vaccine against cytomegalovirus may help to prevent many cases of schizophrenia,” says Professor of Medical Genetics at Aarhus University, Anders Børglum.
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Thoughts On The Viral Theory Of Schizophrenia
Hello,I was wondering if there are any tests that can be performed on parents to identify if they are carrying a higher risk of having anything in their genes that could transmit schizophrenia or another disorder to their babies?
I was also wondering the same thing as Alejandro stated earlier. In my psychology class this semester we discussed the predisposing factors and conditions that contribute to developing mental disorders such as schizophrenia, but no biological factors were discussed, with the exception of genetics. This was also the case for other mental disorders. Im wondering if finding ways to treat this viral infection would result in a significant change in the frequency of schizophrenia cases.
Thats quite interesting; I hadnt realized that certain viral infections affected the fetus during birth and not during prenatal development. I had never considered the ability of the placenta to selectively prevent the passage of certain substances. This of course makes a lot of sense due to viruses ability to infect different types of cells depending on their specific structure.
I found the article very interesting. It makes me wonder what other psychological disorders can be linked to viral theories.
Just wondering, what do unregulated and downregulated mean?
Constraints On Human Studies
A formidable obstacle to establishing a causal relationship between viral infections and the immune abnormalities in schizophrenia is the latency between the putative infection and psychiatric diagnosis. An improved approach is to study patients during their first psychotic episode, or to concentrate on children manifesting schizotypal symptoms or motor abnormalities thought to presage the disease. Even in these cases however, there is an uncertain relationship between the immune abnormalities detected, and the fetal or neonatal immune response to a virus. Analogous caveats apply to neuro-imaging studies, which typically take a macroscopic snapshot of the brain during chronic disease. While there is a recognized need for longitudinal neuromorphometric studies of children and adolescents at risk for schizophrenia, ethical considerations limit the types of neuroradiologic data which can be obtained from this pre-adult population that is not actively manifesting a serious psychiatric disorder. And despite the instrumental role of neuropathological and neurochemical studies in re-focusing schizophrenia research on brain mechanisms, human postmortem studies characterize predominately end-stage disease, and hence cannot untangle the interwoven succession of events occurring upon a viral or bacterial infection of the developing brain.
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Viral Infections And Autoimmunity
An alternative explanation for the finding of increased antibody titers in schizophrenia is that these patients are predisposed toward more vigorous B-cell responses, and consequently prone to develop autoantibodies. Studies of lymphocyte subsets in schizophrenia patients have found an increase in B cells, as well as a subset of patients who have elevated CD5+ B cells,, a cell type thought to be involved in auto-antibody production. Nevertheless, these data have not been consistently replicated, and there is even evidence of impaired immune responses in schizophrenia., Controversy also surrounds data from various laboratories demonstrating autoantibodies against brain constituents of schizophrenia patients.,,, Numerous brain regions have been implicated as targets of autoimmunity. In a recent study, anti-hippocampal antibodies were found to correlate with low IL-2 responses suggesting an autoimmune phenotype in a subgroup of schizophrenia patients.
Brain Morphology And Polyi: C Exposure
Brain structural abnormalities in PolyI:C exposed offspring have also been noted. Abnormal proliferation of cortical progenitor cells and impaired expression of Pak6, a regulator of gene transcription, have been found in the cerebral cortex in the offspring of mice exposed to PolyI:C injection . Additionally, altered development of the cerebellum , has been observed. Other groups have demonstrated concordant neuroanatomical abnormalities, such as ventriculomegaly, between offspring of rodents exposed to PolyI:C during pregnancy and patients with schizophrenia . Prenatal PolyI:C exposure has also been shown to reduce the number of Reelin and Parvalbumin positive cells in the medial prefrontal cortex following exposure on E9 and E17 and in the hippocampal formation and dentate gyrus following exposure on E9 .
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What Are The Causes Of Schizophrenia
If you or a loved one has schizophrenia, its natural to wonder why. Where did this come from? Why me? Why my loved one? What are the causes of schizophrenia?
Doctors and researchers, too, want to know why. Theyre working hard to discover the answer to get to the root of this serious mental illness. The more they understand about what causes schizophrenia, the better they can help the people living with it.
Infectious Agents In Schizophrenia And Bipolar Disorder
E. Fuller Torrey, MDPsychiatric Times
The idea that schizophrenia and bipolar disorder might be caused by infection is not new. New research on infectious agents in patients with schizophrenia and bipolar disorder has implications for psychiatric clinicians.
The idea that schizophrenia and bipolar disorder might be caused by infection is not new. This was a prominent hypothesis in the early years of the last century. For example, an article entitled, Is insanity due to a microbe? was published in Scientific American as early as 1896. Research to test this hypothesis by identifying causative viruses was already being conducted by the 1930s, when data were reported from experiments in which cerebrospinal fluid from patients with schizophrenia was injected into rabbit brains.1
New research in the field continues, aided increasingly by impressive technologic advances in microbiology and virology. As recently as the past decade, reports documented the presence of influenza virus, rubella virus, bovine disease virus, and other infectious agents in patients with schizophrenia and bipolar disorder, as well as the presence of other infectious agents in childhood pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections and obsessive-compulsive disorder.
Background and rationale
Herpes simplex viruses
Implications for clinicians
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Have Researchers Found A New Risk Factor For Schizophrenia
Scientists have located an intriguing link between schizophrenia and the Epstein-Barr virus, a type of herpes virus. Now, they need to determine which way the risk lies.
In a new study, specialists from Johns Hopkins Medicine in Baltimore, MD, and the Sheppard Pratt Health System in Townson, MD, found evidence that links schizophrenia with the Epstein-Barr virus.
As the scientists report in a paper published in the Schizophrenia Bulletin, they saw higher levels of antibodies against the Epstein-Barr virus in the bodies of those with schizophrenia than in those of people without any mental health conditions.
The higher level of antibodies suggests exposure to the virus, but it is unclear which way the risk runs that is, whether infection with the Epstein-Barr virus renders people more vulnerable to schizophrenia, or whether schizophrenia impacts the immune system and exposes people to infections.
We are interested in the role of infectious agents such as Epstein-Barr virus in schizophrenia and other serious psychiatric disorders, so we did this study to look at the associations, says senior study author Dr. Robert Yolken.
environmental factors including exposure to infections can raise schizophrenia risk.
Abnormalities In Neurotransmitter Systems
Understandably, the belief that brain neurotransmitter abnormalities are involved in the etiopathogenesis of schizophrenia is well ensconced among psychiatric researchers and clinicians. Although this belief finds support in neurochemical studies and a massive literature in pre-clinical and clinical psychopharmacology,,, a unifying hypothesis linking neurotransmitter abnormalities with neurodevelopmental insults and the neuropsychological manifestations of schizophrenia has not been forthcoming, particularly with regard to the role of virus infections.
Investigations of excitatory neurotransmitters in schizophrenia have produced a confusing and discrepant body of data. A decrement in glutamatergic function is implied by the finding that glutamate levels are decreased in the hippocampus, prefrontal cortex and CSF,, but these studies have not been consistently replicated, and there may be increased levels of glutamate in some brain regions., Postmortem studies demonstrating a relative decrease of hippocampal complexin II , argue that glutamatergic synapses are impoverished in the disease. This decrement, however, may not be uniformly expressed because the opposite is suggested by increased levels of glutamate reuptake sites in frontal and cingulate cortex,, and an elevated density of glutamatergic fibers in the anterior cingulate.
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Experimental Paradigms Of Maternal Infection
While maternal infection is reported to be a risk factor for schizophrenia, controversy remains concerning which biological processes underlie this risk. There is scant evidence for transplacental passage and persistence of the influenza virus in the offspring brain . More likely to be relevant are the effects of infection-induced maternal immune activation on the developing brain .
MIA may lead straightforwardly to damage to the foetal brain during the early stages of neurodevelopment , but may also provide entry into a deviant trajectory of neural development which predisposes offspring to behavioral deficits depending on the intensity of the infection and when in gestation it occurs . MIA-associated abnormalities have been described, sometimes inconsistently, for multiple brain cell types, all of which are implicated across psychiatric disorders from postmortem data and genetic studies to a greater or lesser extent: Schwann cells , astrocytes and microglia , hippocampal GABAergic cells , dopaminergic neurons , and parvalbumin interneurons .
Gene Expression: the breadth of gene expression changes was greater the later in embryonic development infection occurred; for example embryonic day 16 or 18 infection disrupted more genes, across more brain regions, than did E7 infection. Furthermore, infection at later embryonic stages disrupted expression of genes involved in myelination and implicated in schizophrenia risk.
Neuroinflammation Oxidative Stress And Schizophrenia
While peripheral immune activation recruits inflammatory mediators near the site of insult, this type of activation is capable of activating immune markers in the brain, such as microglia and cytokines . Neuroinflammation as a response to bacterial and viral infections is often described as the accumulation of mobile innate and/or adaptive immune cells present in tissue that have circulated through the bloodstream . These mobile cells, which may be macrophages or neutrophils possess powerful tissue-destructive effects .
Oxidative stress is also thought to play a role in schizophrenia , although the results are somewhat mixed. Several reports have shown reductions in antioxidant enzymes in schizophrenia while other reports have documented no change , or increased antioxidant presence in individuals with schizophrenia .
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How Genes And Microbes Interact
Despite more than a century of research, the genetic basis of psychotic disorders is not well understood. For schizophrenia, recent research has focused on the search for genetic mutations and polymorphisms as causes. This research is based on multiple family studies indicating that schizophrenia has a high degree of heritability; it has been stimulated by the wealth of genetic information that has become available as part of the human genome project. The search for specific genes associated with schizophrenia has also been fueled by findings from linkage studies indicating that some regions of the human genome are inherited nonrandomly in family members who have schizophrenia.
For this reason, it is important to elucidate nongenetic factors that might contribute to schizophrenia. Of particular importance are environmental influences that might interact with genetic factors and thus be applicable to a disease such as schizophrenia, which has a high degree of heritability. The integration of environmental risks might increase the odds ratios of genetic associations in specific populations of exposed individuals and hence increase the likelihood of identifying true positive associations.
As discussed above, there are a number of infectious agents, which have been associated with schizophrenia. This review focuses on Toxoplasma and CMV, since they meet the criteria discussed above and have been associated with schizophrenia in different populations
Genetic Causes Of Schizophrenia
Many genes play a role in your odds of getting schizophrenia. A change to any of them can do it. But usually, itâs several small changes that add up and lead to a higher risk. Doctors arenât sure how genetic changes lead to schizophrenia. But theyâve found that people who have the disorder may be more likely to have problems in their genes that may interfere with brain development.
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Influenza: Structure And Pathophysiology
The influenza virus is an enveloped RNA virus from the family Orthomyxoviridae, with three genera, influenza A, B, and C . Given that influenza type A is responsible for pandemics historically linked to schizophrenia and psychotic symptoms , we will focus on this alone. Influenza A viruses are classified into subtypes based on the antigenic properties of their envelope glycoproteins , hemagglutinin, and neuraminidase. The viral envelope is a lipid membrane derived from plasma membrane of an infected host cell. Influenza strain targets also differ. Notably, the H5N1 virus and other avian-derived strains are neurotropic while H1N1 is thought not to be .
Figure 1 Structure of the influenza virus.
For infection to be successful, hemagglutinin binds the influenza virus to its receptors, sialyloligosaccharides, on the host cell surface. The viral envelope and the host cell membrane fuse giving the viral RNA access to the host cell . Neuraminidase facilitates virus release . Following the production of viral particles in the nucleus of the host cell, the host cell lyses and dies . Protective immune responses from the cell occur; the viral hemagglutinin, neuraminidase, and matrix 2 proteins are targeted by antibodies; matrix 1 proteins are targeted by T cells ; and nucleoproteins are targeted by T cells and nonneutralizing antibodies .