Combination of two environmental factors contributes to schizophrenia

The interplay between an infection during pregnancy and stress in puberty plays a key role in the development of schizophrenia, as behaviourists from ETH Zurich demonstrate in a mouse model. However, there is no need to panic.

Around one per cent of the population suffers from schizophrenia, a serious mental disorder that usually does not develop until adulthood and is incurable. Psychiatrists and neuroscientsist  have long suspected that adverse enviromental factors may play an important  role in the development of schizophrenia. Prenatal infections such as toxoplasmosis or influenza, psychological, stress or family history have all come into question as risk factors. Nevertheless, until now researchers were unable to identify the interplay of the individual factors linked to this serious mental disease. 

However, a research group headed by Urs Meyer, a senior scientist at the Laboratory of Physiology & Behaviour at ETH Zurich, has now made a breakthrough: for the first time, they were able to find clear evidence that the combination of two environmental factors contributes significantly to the development of schizophrenia-relevant brain changes and at which stages in a person's life they need to come into play for the disorder to break out. The researchers developed a special mouse model, with which they were able to simulate the processes in humans virtually in fast forward. The study has just been published in the journal Science.   

Interplay between infection and stress

The first negative environmental influence that favours schizophrenia is a viral infection of the mother during the first half of the pregnancy. If a  child with such a prenatal infectious history is also exposed to major stress during puberty, the probability that he or she will suffer from schizophrenia later increases markedly. Hence, the mental disorder needs the combination of these two negative environmental influences to develop. "Only one of the factors - namely an infection or stress - is not enough to develop schizophrenia," underscores Meyer.   

The infection during pregnancy lays the foundation for stress to "take hold" in puberty. After all, the mother's infection activates certain immune cells of the central nervous system in the brain of the foetus: microglial cells, which produce cytotoxins that alter the brain development of the unborn child.       

Mouse model provides important clue

Once the mother's infection subsides, the microglial cells lie dormant but have developed a "memory". If the adolescent suffers severe, chronic stress during puberty, such as sexual abuse or physical violence, the microglial cells awake and induce changes in certain brain regions through this adverse postnatal stimulus. Ultimately, these neuroimmunological changes do not have a devastating impact until adulthood. The brain seems to react particularly sensitively to negative influences in puberty as this is the period during which it matures. "Evidently, something goes wrong with the 'hardware' that can no longer be healed," says Sandra Giovanoli, who, as a doctoral student under Urs Meyer, did the lion's share of the work on this study.

The researchers achieved their ground-breaking results based on sophisticated mouse models, using a special substance to trigger an infection in pregnant mouse mothers to provoke an immune response. Thirty to forty days after birth - the age at which the animals become sexually mature, which is the equivalent of puberty - the young animals were exposed to five different stressors which the mice were not expecting. This stress is the equivalent of chronic psychological stress in humans.

Diminished filter function

Afterwards, the researchers tested the animals' behaviour directly after puberty and in adulthood,. As a control, the scientists also studied mice with either an infection or stress, as well as animals that were not exposed to either of the two risk factors.

When the researchers examined the behaviour of the animals directly after puberty, they were not able to detect any abnormalities. In adulthood, however, the mice that had both the infection and stress behaved abnormally. The behaviour patterns observed in the animals are comparable to those of schizophrenic humans. For instance, the rodents were less receptive to auditory stimuli, which went hand in hand with a diminished filter function in the brain. The mice also responded far more strongly to psychoactive substances such as amphetamine.

Environmental influences more significant again

"Our result is extremely relevant for human epidemiology," says Meyer. Even more importance will be attached to environmental influences again in the consideration of human disorders - especially in neuropsychology. "It isn't all genetics after all," he says.  

Although certain symptoms of schizophrenia can be treated with medication, the disease is not curable. However, the study provides hope that we will at least be able to take preventative action against the disorder in high-risk people. The study is a key foundation upon which other branches of research can build.

The ETH Zurich researchers also stress that the results of their work are no reason for pregnant women to panic. Many expecting mothers get infections such as herpes, a cold or the flu. And every child goes through stress during puberty, whether it be through bullying at school or quarrelling at home. "A lot has to come together in the 'right' time window for the probability of developing schizophrenia to be high," says Giovanoli. Ultimately, other factors are also involved in the progress of the disease. Genetics, for instance, which was not taken into consideration in the study, can also play a role. But unlike genes, certain environmental influences can be changed, adds the doctoral student; how one responds to and copes with stress is learnable.   

Source: ETH Zurich

Comments

  1. Frank Lekstutis Frank Lekstutis United States says:

    How do they explain all the genetic research finding mutations in the genes that control nerve cell growth in the first 3 months of life after conception?

  2. Segundo Mesa Castillo Segundo Mesa Castillo Cuba says:

    In agreement with our previous reports the advances obtained in understanding central nervous system (CNS) viral infections make viruses attractive etiological candidates for the prenatal origin of
    schizophrenia. Among these candidates is Herpes Simplex Hominis type I Virus (HSV-1) due its capacity to remain latent with periodic reactivation, its affinity for the limbic system, the region of
    the brain involved in schizophrenia, its reactivation by endocrine changes, stress, radiation and immune alterations and for its relation to genetic predisposition. Presumptive evidence for a viral
    etiology requires the demonstration of a virus, antigen or viral antibody. Our electron and immunoelectronmicroscopic
    observations of viral particles and HSV-1 antigen in the temporal lobe of the brain of dead adults schizophrenic patients, of aborted fetuses from schizophrenic mothers and in experimental animals inoculated with cerebrospinal fluid [CSF] from schizophrenic patients made us to consider this virus as an etiological agent since Koch postulates have been partially fulfilled.

  3. Segundo Mesa Castillo Segundo Mesa Castillo Cuba says:

    Schizophrenic monozygotic twins concordance  is of only 45% although both twins share 100% of the derived genoma of a single zygote for what the discordance in monozygotic twins is related to the influence of prenatal environmental factors independently of genetic factors. These prenatal environmental factors are related to the alterations in the brain and  the skin more frequently observed in patients since both tissues are derived from the embryonic ectoderm. This fact explains the anomalies of the nervous system together with anomalies of the hair, face, hands and feet more frequently observed in schizophrenics discordant twin than in the normal population. Among the  environmental factors virus occupies a more and more excellent position for the results obtained in clinical observations in human and in experimental animals. A virus acting in this first phase of  development, especially during the 2do. pregnancy trimester can explain the anomalies observed in both structures derived of the embryonic ectoderm in the affected twin. In the present work the results obtained in an ultrastructural study are exposed in samples of the brain of two monozygotic twin fetuses with strong antecedents of schizophrenia in their family. The obtained findings indicate an infection for the virus herpes simplex hominis type I [HSV1] in the brain of one of the twins and mitochondria alterations. The obtained results can explain the discordance of the illness found in the postnatal clinical and epidemiologic studies. It should be considered their relation to the viral etiology to be the first direct evidence of virus in the brain of a fetus from a schizophrenic mother with important biological load of family schizophrenia.

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