Editors' ChoicePsychiatry

Can the past predict the future?

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Science Translational Medicine  13 Apr 2016:
Vol. 8, Issue 334, pp. 334ec60
DOI: 10.1126/scitranslmed.aaf6939

The etiology of most neuropsychiatric disorders is increasingly accepted to be a combination of genetic and environmental factors. Among these, exposure to prenatal adverse environmental effects such as toxins, stress, or infection has been suggested to be risk factors for disorders such as autism and schizophrenia. Simulation of viral infections by injection of a viral mimic during gestation in rodents is a well-established way to study potential behavioral deficits and their pathophysiology in the offspring. Using a maternal infection mouse model, Weber-Stadlbauer et al. now show that the prenatal environment of a grandparent could have detrimental consequences on several generations of offspring. The fact that the effects were observed up to three generations later suggests possible transgenerational inheritance. Interestingly, these behavioral changes were transmitted through the paternal lineage. An intriguing result was that differences in behavioral patterns were found between generations, with new behavioral defects emerging only in the second- and third-generation offspring. These behavioral phenotypes were associated with changes in transcriptional profiles in brain tissue, with both common and generation-specific transcriptional changes observed. The common changes included alterations in the dopaminergic signaling pathway, whereas generation-specific changes involved alterations in G protein signaling in the first generation and glutamatergic signaling in the second generation. Dysregulation of these pathways has been associated with several neuropsychiatric disorders such as schizophrenia, bipolar disorder, and autism. Although epidemiological studies suggest that maternal exposure to infection per se is not associated with a higher prevalence of psychiatric disorders, it is believed to be a trigger mechanism in genetically susceptible individuals as well as a predisposing agent for additional environmental insults (multiple-hit hypothesis). The study by Weber-Stadlbauer et al. presents a way to investigate the transgenerational transmission of disease risk. In addition, given that maternal immune activation is known to induce different behavioral effects based on timing of infection, the study of the effects of infection in the offspring at different time points during gestation would allow for characterization of critical periods during development when susceptibility to disease is higher. It will be important to characterize the mechanisms responsible for disease risk transmission. A plausible explanation pinpoints epigenetic processes. Epigenetics, the regulation of gene expression without changes in the DNA sequence, is an expanding field of study to address the influence of environment on nongenetic heritability of behavioral traits and disease susceptibility. Study of the responsible mechanisms could guide interventions to prevent or ameliorate neuropsychiatric disease risk.

U. Weber-Stadlbauer et al., Transgenerational transmission and modification of pathological traits induced by prenatal immune activation. Mol. Psychiatry 10.1038/mp.2016.41 (2016). [Abstract]

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