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 environmental 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 fetus: 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.
- S. Giovanoli, H. Engler, A. Engler, J. Richetto, M. Voget, R. Willi, C. Winter, M. A. Riva, P. B. Mortensen, M. Schedlowski, U. Meyer. Stress in Puberty Unmasks Latent Neuropathological Consequences of Prenatal Immune Activation in Mice. Science, 2013; 339 (6123): 1095 DOI: 10.1126/science.1228261
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