Pregnant mice who were deprived of docosahexaenoic acid (DHA) and arachidonic acid (AA) gave birth to offspring that developed behavioural symptoms of early psychosis (the precursor to schizophrenia) in humans, found researchers from the RIKEN Brain Science Institute in Japan.
Writing in Translational Psychiatry, the scientists found that the likely mechanism was epigenetic downregulation of nuclear receptor genes RXR and PPAR induced by deficiencies of these polyunsaturated fatty acids (PUFAs). This in turn dysregulated other genes responsible for the gamma-aminobutyric acid (GABA) neurotransmitter system and oligodendrocytes (cells surrounding the neurons); alteration of which has been identified in humans with schizophrenia.
“We showed that PUFA deficiency during the early neurodevelopmental period in mice could model the prodromal state of schizophrenia most likely through epigenetic silencing of nuclear receptor genes, thereby dysregulating downstream neural gene expression,” wrote first author Dr. Motoko Maekawa.
The concept that intergenerational disease risk for offspring is established before, and for up to 1000 days after, conception is known as the ‘developmental origins of health and disease’ (DOHaD) hypothesis. The researchers suggest that this is the first study to identify the molecular mechanisms of schizophrenia within the DOHaD context.
"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 Maekawa.
Applications and next steps
A possible future applications arising from study findings would be the development of drugs to target nuclear receptors. Nevertheless, the team emphasised the importance of adequate PUFA intake during early pregnancy.
“The current results support the hypothesis of beneficial effects of supplementation of AA and DHA in neurodevelopmental stages,” noted the authors.
As next steps, they suggested that the individual and combined effects of DHA and AA should be clarified, together with identifying critical doses, while identifying “the timing of the ‘epigenetic window’, a critical period for the generation of epigenetic changes, remains an important unanswered question.”
Source: Translational Psychiatry
Published online., doi: 10.1038/tp.2017.182
“Polyunsaturated fatty acid deficiency during neurodevelopment in mice models the prodromal state of schizophrenia through epigenetic changes in nuclear receptor genes”
Authors: Motoko Maekawa, Takeo Yoshikawa et al.