AsianScientist (Sep. 13, 2017) – In a study published in Translational Psychiatry, scientists in Japan have discovered how changes in nutrition during early mouse pregnancy lead to offspring that develop schizophrenic-like symptoms as adults.
Harmful conditions during pregnancy are known to affect the health of offspring, even resulting in adult-onset diseases. This concept is known as the development origin of health and disease (DOHaD). Historical evidence has also shown that schizophrenia diagnoses double in the next generation after a famine.
In this study, Professor Takeo Yoshikawa and his team at RIKEN in Japan studied how malnutrition affected early developmental changes the brain. 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. The adult mice whose mothers were deprived of DHA and AA showed low levels of motivation, depression, impaired memory, and abnormal brain function in the prefrontal cortex, similar to the symptoms of schizophrenia.
“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,” said Dr. Motoko Maekawa of RIKEN who is the first author of the study.
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 were found to be related to oligodendrocytes, cells in the brain that surround neurons and help with the transmission of signals in the brain. Additionally, the expression of genes affecting the GABA neurotransmitter system were altered in ways that mimicked findings from the postmortem brains of people with schizophrenia.
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. Analysis of hair follicles from two separate populations of human patients with schizophrenia showed that they too exhibited reduced expression of the same nuclear receptor genes.
The researchers then demonstrated that the abnormal expression of oligodendrocyte-related genes could be directly traced to the low expression of these nuclear receptors, which, in turn, was associated with higher levels of DNA methylation, a common way to regulate gene expression. Because of these epigenetic changes, the altered diet succeeded in creating long-lasting changes in gene expression.
Importantly, when the scientists 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,” said Maekawa. “The next step 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.”
The article can be found at: Maekawa et al. (2017) Polyunsaturated Fatty Acid Deficiency During Neurodevelopment in Mice Models the Prodromal State of Schizophrenia through Epigenetic Changes in Nuclear Receptor Genes.
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Source: RIKEN; Photo: Pixabay.
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