Animal models of gene-environment interaction in schizophrenia: A dimensional perspective

Abstract

Schizophrenia has long been considered as a disorder with multifactorial origins. Recent discoveries have advanced our understanding of the genetic architecture of the disease. However, even with the increase of identified risk variants, heritability estimates suggest an important contribution of non-genetic factors. Various environmental risk factors have been proposed to play a role in the etiopathogenesis of schizophrenia. These include season of birth, maternal infections, obstetric complications, adverse events at early childhood, and drug abuse. Despite the progress in identification of genetic and environmental risk factors, we still have a limited understanding of the mechanisms whereby gene-environment interactions (G × E) operate in schizophrenia and psychoses at large. In this review we provide a critical analysis of current animal models of G × E relevant to psychotic disorders and propose that dimensional perspective will advance our understanding of the complex mechanisms of these disorders.

Keywords: Animal models; Dimensional perspective; Psychotic disorders; RDoC.

Figure 1. Animal models of GxE in schizophrenia

The figure displays some major outcomes of GxE in different animal models. - New phenotype The DN-CAMKII-DISC1 x poly I:C combination demonstrates that GxE may result in a new phenotype that was not previously observed in mutant mice without an environmental challenge. For example, prenatal (GD9) exposure to maternal immune activation of mutant DISC1 mice produced the neurobehavioral alterations consistent with affective disorders (arrow in the green area) in mice that show more schizophrenia-like phenotypes without maternal immune activation (red arrow). - Stronger phenotype The Nurr1-HET-poly x I:C combination demonstrates the exacerbated phenotypes in mutant mice exposed to prenatal immune activation at GD17. Both genetic mutation and immune challenge are able to produce some schizophrenia-like neurobehavioral alterations (thin red arrows) but those pre-existing changes become significantly exacerbated when both factors are combined in mice. - Emerging phenotype The DN-PrP-DISC1 x adolescent stress or COMT x adolescent cannabis combinations produce the phenotypes that were not observed when either mutation or environmental treatment was used separately. - Protective effects of GxE Early maternal separation (PND2-6) affected social behavior in WT mice but had not effects in reeler mice. The figure also depicts the main idea of the review that different combination of genetic risk factors and environmental adversities result in neurobehavioral abnormalities that represent a continuum of behavioral disorders. These behavioral alterations should not be categorized as specific diseases because phenotypic changes in mice (much like the human conditions) seem to be more accurately described by dimensional perspectives. Abbreviations: HET – heterozygous mice, DN – dominant negative mutant human DISC1; CAMKII or PrP – the promoters used to express DN-DISC1 Abbreviation list: GEI – gene-environment interaction DSM-V - the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders GWAS - genome-wide-association studies SNP - single nucleotide polymorphism PGC - Psychiatric Genomics Consortium MHC - the Major Histocompatibility Complex CNV - copy number variations DISC1 - Disrupted-In-Schizophrenia 1 LOD - logarithm of odds MIA – maternal immune activation HSV – herpes simplex virus CMV – cytomegalovirus HLA - the human leucocyte antigen HERV - human endogenous retroviruses FOX2P - the Forkhead box protein P2 gene MRI - magnetic resonance imaging METH – Methamphetamine ADHD – attention deficit hyperactivity disorder TLR – toll-like receptor DOX – doxycycline GD – gestation day mPFC - the medial prefrontal cortex Nurr1 - The nuclear receptor related 1 protein