Abstract
DISC1 was discovered in a Scottish pedigree in which a chromosomal translocation that breaks this gene segregates with psychiatric disorders, mainly depression and schizophrenia. Linkage and association studies in diverse populations support DISC1 as a susceptibility gene to a variety of neuropsychiatric disorders. Many Disc1 mouse models have been generated to study its neuronal functions. These mouse models display variable phenotypes, some of them relevant to schizophrenia, others to depression. The Disc1 mouse models are popular genetic models for studying gene-environment interactions in schizophrenia. Five different Disc1 models have been combined with environmental factors. The environmental stressors employed can be classified as either early immune activation or later social paradigms. These studies cover major time points along the neurodevelopmental trajectory: prenatal, early postnatal, adolescence, and adulthood. Various combinations of molecular, anatomical and behavioral methods have been used to assess the outcomes. Additionally, three of the studies sought to rescue the resulting abnormalities. Here we provide background on the environmental paradigms used, summarize the results of these studies combining Disc1 mouse models with environmental stressors and discuss what we can learn and how to proceed. A major question is how the genetic and environmental factors determine which psychiatric disorder will be clinically manifested. To address this we can take advantage of the many Disc1 models available and expose them to the same environmental stressor. The complementary experiment would be to expose the same model to different environmental stressors. DISC1 is an ideal gene for this approach, since in the Scottish pedigree the same chromosomal translocation results in different psychiatric conditions.
Highlights
Both schizophrenia and depression have a strong genetic component but are heavily influenced by the environment
It is more practical to use genetic models with relatively weak phenotypes, such as heterozygotes instead of homozygotes (Ibi et al, 2010; Haque et al, 2012; Lipina et al, 2013; Niwa et al, 2013), or to at least focus on specific assays which are not affected by the G condition on its own (Abazyan et al, 2010)
The same is true for the choice of the environmental stressor—to detect G × E effects it is useful to choose a regime which is sub-optimal on its own, such as changing the administration route (Abazyan et al, 2010) or reducing the dose (Lipina et al, 2013) of polyribocytidylic acid (polyI):C, or developing a new, milder form of social stress paradigm (Niwa et al, 2013)
Summary
Both schizophrenia and depression have a strong genetic component but are heavily influenced by the environment. CaMK-DN-DISC1 mice were injected with polyI:C daily from postnatal day 2–6, which corresponds to the second trimester of human brain development (http:// translatingtime.net) This paradigm of neonatal polyI:C injection on its own elicits behavioral abnormalities including impairments in PPI, novel object recognition and social behavior in mice tested at 10–12 weeks of age (Ibi et al, 2009). PrP-DN-DISC1 mice with 3-week isolation (G × E) displayed multiple behavioral deficits, including decreased prepulse inhibition, increased immobility in a forced swim test, and an augmented locomotion response to methamphetamine challenge when compared to the control, G, and E groups These abnormal phenotypes resulted from synergistic gene-environment interaction at the cellular level, rather than any gross anatomical or histological mechanism. L100P mice displayed a deficit in PPI, and both L100P and Q31L mice displayed disruptions in LI, but CSD did not exacerbate either endophenotype for any group
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