Prenatal Interaction of Mutant DISC1 and Immune Activation Produces Adult Psychopathology

Abstract

Background-Gene-environment interactions (GEI) are involved in the pathogenesis of mental diseases. We evaluated interaction between mutant human Disrupted-In-Schizophrenia-1 (mhDISC1) and maternal immune activation implicated in schizophrenia and mood disorders.

Neurodevelopment, GABA System Dysfunction, and Schizophrenia

“…Therefore, one might argue that the different genetic susceptibilities will define the disease phenotype in a G Â E manner, in which the environment can be considered a 'disease-predisposer', and the genetic susceptibility is the 'disease-specifier' (Figure 1). This view has some support from animal studies, where MIA, in conjunction with a schizophrenia-susceptibility genotype (such as DISC1), mirrors the late-onset behavioral abnormalities observed in schizophrenia (Abazyan et al, 2010;Ibi et al, 2010). Finally, investigation of the pathophysiology of schizophrenia with animal models will remain a major challenge.…”

“…Furthermore, interferon-induced transmembrane protein 3 (IFITM3) expression in astroglia appears to be involved in mediating this MIA-IL-6 response (Ibi et al, 2013), which is interesting considering IFITM3 is increased in schizophrenia and negatively correlated with GABAergic gene expression (Horvath and Mirnics, 2014a;Siegel et al, 2013). Furthermore, the delayed molecular and behavioral effects of MIA in adulthood can be revealed in at-risk genotypes as mice with mutant forms of DISC1 display additional phenotypes after in utero exposure to polyinosinic:polycytidylic acid (poly I:C), a double-stranded RNA viral mimetic and cytokine inducer (Abazyan et al, 2010;Ibi et al, 2010;Lipina et al, 2013). The immune system, GABAergic systems, and schizophrenia risk genes may be an important point of G Â E interaction in schizophrenia.…”

Maternal Immune Activation during Gestation Interacts withDisc1Point Mutation to Exacerbate Schizophrenia-Related Behaviors in Mice

“…Disrupted-In-Schizophrenia-1 (DISC1) is a prominent schizophrenia susceptibility gene, which regulates progenitor cell proliferation, migration, and differentiation (Chubb et al, 2008;Brandon and Sawa, 2011). Recent studies have shown interactions between MIA and DISC1, using transgenic mice expressing a dominant-negative DISC1 (DN-DISC1) (Ibi et al, 2010) and a mouse model with inducible expression of mutant human DISC1 (mhDISC1) (Abazyan et al, 2010). MIA triggered behavioral and cellular alterations related to schizophrenia in adult DN-DISC1 offspring without effect on WT mice (Ibi et al, 2010;.…”

“…MIA triggered behavioral and cellular alterations related to schizophrenia in adult DN-DISC1 offspring without effect on WT mice (Ibi et al, 2010;. The combination of MIA with postnatal expression of hmDISC1 resulted in anxiousdepressive phenotypes (Abazyan et al, 2010). Although these two studies used different approaches to MIA and different DISC1 modifications, they illustrate the interactions between DISC1 and the maternal immune system during development.…”

Inside the minds of mice and men

“…The fostered mice showed no social deficits as adults, but other relevant symptoms, such as repetitive grooming, were not reduced. And when a mutant version of DISC1, the first gene to be implicated in schizophrenia, is present in mice whose mother's immune system has been stressed during pregnancy, the offspring exhibit symptoms of affective disorders and autism 6 . Without the environmental stressors, they show symptoms of schizophrenia.…”