Alternative models for transgenerational epigenetic inheritance: Molecular psychiatry beyond mice and man

Abstract

Mental illness remains the greatest chronic health burden globally with few in-roads having been made despite significant advances in genomic knowledge in recent decades. The field of psychiatry is constantly challenged to bring new approaches and tools to address and treat the needs of vulnerable individuals and subpopulations, and that has to be supported by a continuous growth in knowledge. The majority of neuropsychiatric symptoms reflect complex gene-environment interactions, with epigenetics bridging the gap between genetic susceptibility and environmental stressors that trigger disease onset and drive the advancement of symptoms. It has more recently been demonstrated in preclinical models that epigenetics underpins the transgenerational inheritance of stress-related behavioural phenotypes in both paternal and maternal lineages, providing further supporting evidence for heritability in humans. However, unbiased prospective studies of this nature are practically impossible to conduct in humans so preclinical models remain our best option for researching the molecular pathophysiologies underlying many neuropsychiatric conditions. While rodents will remain the dominant model system for preclinical studies (especially for addressing complex behavioural phenotypes), there is scope to expand current research of the molecular and epigenetic pathologies by using invertebrate models. Here, we will discuss the utility and advantages of two alternative model organisms–Caenorhabditis elegans and Drosophila melanogaster–and summarise the compelling insights of the epigenetic regulation of transgenerational inheritance that are potentially relevant to human psychiatry.

Keywords: Transgenerational inheritance, Epigenetics, Invertebrate models, Caenorhabditis elegans, Drosophila melanogaster, Environmental stress

Core Tip: Psychiatry research is only beginning to identify the complex epigenetic pathologies across various conditions that may regulate symptomatology. Epigenetics may account for certain conditions that are highly heritable but are not fully accounted for by genetics. Preclinical animal models are a necessary tool to accelerate our understanding of molecular mechanisms and for developing new therapeutic options. Simple behavioural and neurobiological assays combined with high levels of functional gene conservation and rapid generation time in easily genetically manipulated organisms make Caenorhabditis elegans and Drosophila melanogaster excellent systems to model transgenerational epigenetic inheritance phenotypes.