06 Sep 2017 --- Researchers 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 from the RIKEN Brain Science Institute in Japan shows how deprivation of two polyunsaturated fatty acids during early gestation can have long-lasting effects on offspring through specific changes in gene expression.
Harmful conditions during pregnancy are known to affect the health status of offspring, even resulting in adult-onset diseases – for example, prenatal alcohol exposure has been linked to an increase in the likelihood of addiction. This concept – known as the Development Origin of Health and Disease (DOHaD) – could explain why rates of schizophrenia have been observed to double after famines, the RIKEN press release points out.
In order to develop effective treatments for schizophrenia, Takeo Yoshikawa and his team at RIKEN report that they are researching exactly how malnutrition during early development changes the brain.
“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,” study first author Motoko Maekawa notes.
Linking nutrients to schizophrenia The first step to figuring out the “how” of the study was to determine the most likely nutrient whose deficiency is related 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. RIKEN reports that the team tested their theory by depriving pregnant mice of DHA and AA and testing whether their adult offspring shared characteristics shown 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 reports that it looked next at how DHA and 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 gamma-aminobutyric acid (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.
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, it was found that the altered diet succeeded in creating long-lasting changes in gene expression.
The results of the prenatal study come at a time when it has already been suggested that the prenatal supplements industry should review product formulations. Meanwhile, omega 3 and omega 6 continue to be linked with positive health claims, as was shown when Bunge’s soybean health oil claim was approved by the US FDA based on a petition that included a summary of recent major clinical studies showing the potential benefits of soybean oil to heart health. The petition was based partly on its high concentration of polyunsaturated omega 6 and omega 3 fatty acids versus other oils and fats.
The study, “Polyunsaturated fatty acid deficiency during neurodevelopment in mice models the prodromal state of schizophrenia through epigenetic changes in nuclear receptor genes,” is published in Trans Psychiatry.
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