Researchers have discovered a mechanism in mice whereby lack of nutrients in early pregnancy gives rise to schizophrenia-like symptoms in adult offspring. The mechanism, which involves a sequence of altered gene expressions, results from lack of two omega-3 and omega-6 fatty acids in the mother's diet.

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Lack of omega-3 and omega-6 fatty acids in pregnancy may cause changes in gene expression that lead to adult-onset diseases in offspring.

The researchers, from the RIKEN Brain Science Institute in Tokyo, Japan, report their findings in the journal Translational Psychiatry.

Schizophrenia is a severe long-term disorder that can disrupt thinking, perception, emotions, and behavior. There is currently no cure for the disease, but there are treatments that can help patients to manage their symptoms and lead an independent, productive life.

Worldwide, there are around 21 million people with schizophrenia, which typically starts in late adolescence or early adulthood.

Scientists probing the causes of the disease believe that it is a highly complex disorder, perhaps even a "collection of different disorders."

The general consensus is that schizophrenia arises from a combination of causes, including genetic factors and environmental influences such as exposure to viruses and difficulties during birth.

Altered nutrition

There is also a growing understanding that altered nutrition at specific times during prenatal development can increase susceptibility to diseases that only appear much later in life.

In the new study, Dr. Takeo Yoshikawa, senior team leader in molecular psychiatry, and colleagues investigated how lack of two nutrients - the omega-3 fatty acid DHA and the omega-6 fatty acid AA - altered the expression of genes involved in brain development before birth.

They chose the two polyunsaturated fatty acids because previous studies have linked them to schizophrenia, and they are known to be abundant in the brain and influence its development.

First, they deprived pregnant mice of DHA and AA and found that their offspring developed schizophrenia-like symptoms in adulthood. These symptoms included depression, memory impairment, and low motivation.

Reduced gene expression

Another hallmark of schizophrenia is dysfunction in the prefrontal cortex, which is a part of the brain that has a number of functions. These include planning, working memory, attention, error-monitoring, decision-making, and social cognition.

When they examined the prefrontal cortex of the schizophrenia-like adult mice, the team found that hundreds of genes had been affected by DHA and AA deprivation.

In particular, they found that DHA and AA deprivation had reduced expression in a group of genes that are also known to be "downregulated" in the brains of people with schizophrenia.

It appeared that lack of the two fatty acids had reduced the influence of the genes by increasing levels of DNA methylation, an "epigenetic process" that places chemical tags on the gene.

The affected genes influence oligodendrocytes, which are cells that surround neurons, or brain cells, and help them to communicate with each other.

Downregulated nuclear receptor genes

Further investigation also revealed that DHA and AA deprivation had altered the expression of genes related to the function of the GABA neurotransmitter, a brain chemical that is involved in brain cell signaling. The alterations mirrored those found in postmortems of the brains of people with schizophrenia.

The team also found that the schizophrenia-like mice had several other downregulated genes that code for nuclear receptors, which are a class of proteins that attach to DNA and trigger protein-building in cells.

The researchers then traced the downregulated nuclear receptor genes to the higher levels of DNA methylation in the genes that influence oligodendrocytes, and which were thus ultimately responsible for their altered expression.

Through this sequence of steps, the team was able to show how a change in diet led to long-lasting alterations in gene expression.

Potential new drug target

The researchers also investigated a possible way to reverse the damage. When they gave some of the affected mice a drug that targets the nuclear receptors, they found that the downregulated genes associated with oligodendrocytes and GABA were upregulated. This coincided with reductions in some behaviors.

First author Motoko Maekawa says, "This was evidence that drugs acting on nuclear receptors can be a new therapy for schizophrenia."

The researchers also found evidence that the same nuclear receptor genes are downregulated in people with schizophrenia. They discovered this by examining hair follicles from two groups of schizophrenia patients.

"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."

Motoko Maekawa