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Prenatal lack of omega-3 and omega-6 fatty acids linked to schizophrenic symptoms in mice


Oily fish Pacific saury Cololabis saira for sale photo by Eric Grafman on CDC site

Researchers at the RIKEN Brain Science Institute in Japan have discovered a process through which changes in nutrition during early mouse pregnancy lead to offspring that develop schizophrenic-like symptoms as adults.


Prenatal malnutrition can have lifelong effects on brain development and function - as well as physical health - via epigenetic 'nutritional programming' effects, which permanently alter gene expression and regulation. 

Poor nutrition during pregnancy is already known to increase risks for schizophrenia and other neurodevelopmental disorders in the unborn child.  By definition, adequate supplies of all essential nutrients are needed for optimal brain development; but previous research has repeatedly linked early life deficiencies in the long-chain omega-3 and omega-6 fats, DHA and AA (both essential for normal brain structure and function) with neurodevelopmental disorders in general, and with schizophrenia in particular.

This new study therefore used an animal model to investigate in more detail how maternal dietary deficiencies of DHA and AA affect brain development, with the aim of identifying specific mechanisms relevant to schizophrenia.

Results showed that feeding mothers-to-be an omega-3 and omega-6 deficient diet during pregnancy led to changes in gene expression and regulation in their offspring, which permanently altered their fatty acid metabolism.

As adults, the offspring showed many behaviours typical of schizophrenia, including low levels of motivation, depression, and impaired memory and cognition.  Importantly, cells from human patients diagnosed with schizophrenia were also found to show similar changes in gene expression and regulation.

The researchers also identified specific cell signalling systems affected by the 'nutritionally programmed' changes in the animals, and were even able to find a possible drug treatment, which their preliminary studies showed might be able to reverse some of these effects. Further research is clearly needed to confirm this, but these are remarkable and promising findings.

This study is the first to link specific prenatal nutrient deficiencies - of the long-chain omega-3 and omega-6 fatty acids DHA and AA - to specific changes in gene expression and cell signalling which persist into adulthood, and which also appear to relate directly to behavioural abnormalities characteristic of schizophrenia in both animals and humans.

It has also identified candidate drugs that might help to mitigate these cell signalling changes. However, this still needs confirmation in more preclinical studies, and only if these confirm efficacy and safety can human clinical trials then be conducted.

Meanwhile, as prevention of schizophrenia would have more benefits than any still-distant possible treatment for this devastating illness, these findings add new weight to the already compelling case for public health policies to improve early life nutrition. 

Maternal deficiencies of omega-3 DHA are now highly prevalent worldwide - and there is already definitive evidence that supplementation in pregnancy reduces prematurity (which raises risks not only for schizophrenia but for numerous chronic mental and physical health disorders) as well as studies showing this would be cost-effective just from the very short-term benefits of fewer pre-term births. 

Deficiencies of omega-6 AA are more common in developing countries, and/or in other populations with predominantly plant-based diets - but as this fatty acid is equally critical to brain and body health, more targeted policies could be used to ensure adequate intakes. 

Read the underlying research here:

See also:

And for more news and research on the importance of omega-3 (and omega-6) fatty acids in early life, and in schizophrenia, please bookmark the following lists, which are regularly updated as new articles are added.

Researchers at the RIKEN Brain Science Institute in Japan have discovered a process through which changes in nutrition during early mouse pregnancy lead to offspring that develop schizophrenic-like symptoms as adults.

Published in Translational Psychiatry, the study shows how deprivation of two polyunsaturated fatty acids during early gestation can have long lasting effects on offspring through specific epigenetic changes in gene expression.

Harmful conditions during pregnancy are known to affect the health of offspring, even resulting in adult-onset diseases.

This concept—the Development Origin of Health and Disease (DOHaD)—can explain why rates of schizophrenia have been observed to double after famines. In order to develop effective treatments for schizophrenia, Takeo Yoshikawa and his team at RIKEN are researching exactly how malnutrition during early development changes the brain.

First author Motoko Maekawa notes that, "our work is the first in the field of psychiatry to identify a molecular cascade that links nutritional environment to disease risk in the context of the DOHaD paradigm."

The first step to figuring out the "how", was to determine the most likely nutrient whose deficiency is related to schizophrenia. Among several candidates that have been linked to schizophrenia, the team chose to study two specific polyunsaturated fatty acids—the omega-3 fatty acid DHA and the omega-6 fatty acid AA—because they are abundant in the brain and are known to be related to brain development.

The team tested their theory by depriving pregnant mice of DHA and AA and testing whether their adult offspring shared characteristics exhibited by people with schizophrenia.

People in the early stages of schizophrenia have several common symptoms, including low levels of motivation, depression, impaired memory, and abnormal brain function in the prefrontal cortex. The adult mice whose mothers were deprived of DHA and AA showed similar symptoms.

As dysfunction in the prefrontal cortex is a hallmark of schizophrenia, the team next looked at how DHA/AA deprivation affects gene expression in that part of the brain.

Among the hundreds of affected genes, they found a group of genes downregulated in people with schizophrenia that were also downregulated in the affected mice.

These genes are related to oligodendrocytes, cells in the brain that surround neurons and help the transmission of signals in the brain. Additionally, expression of genes affecting the GABA neurotransmitter system were altered in ways that mimicked findings from the postmortem brains of people with schizophrenia.

Gene expression can be controlled by a certain class of proteins called nuclear receptors that attach to DNA and initiate the transcription process that builds proteins from the DNA code. When the team conducted further analysis of the fatty-acid deprived mice, they found several nuclear receptor genes related to fatty acids had been downregulated.

It turns out that the abnormal expression of oligodendrocyte-related genes could be traced directly back to the low expression of these nuclear receptors, which in turn could be traced back to higher levels of DNA methylation, a common way to regulate gene expression.

In this way, the altered diet succeeded in creating long-lasting changes in gene expression.

Once they knew which nuclear receptor genes were downregulated, the team could think about how to reverse the process.

When they gave mice a drug that acts on RXR nuclear receptors, they found that oligodendrocyte- and GABA-related genes were upregulated, and that some of the abnormal motor behavior was reduced. "This was evidence that drugs acting on nuclear receptors can be a new therapy for schizophrenia," says Maekawa.

Knowing the genes responsible also gave the team a target to investigate in people with schizophrenia. Analysis of hair follicles from two separate populations of patients with schizophrenia showed that they too exhibited reduced expression of the same nuclear receptor genes.

"The next step," explains Maekawa "is to test the effectiveness of drugs that target these nuclear receptors in patients with schizophrenia, and to investigate how nuclear receptors regulate the function of oligodendrocytes and GABAergic neurons to prevent the development of schizophrenic pathophysiology."

5 September 2017 - MedicalXpress