Following the genes: a framework for animal modeling of psychiatric disorders

Abstract

The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans.

Systematic phenomics analysis of ASD-associated genes reveals shared functions and parallel networks underlying reversible impairments in habituation learning

“…Our data adds to the recent and rapidly expanding use of model organism phenomics to discover the functions of poorly characterized genes identified through genomic sequencing. 44,101,[153][154][155][156][157][158] We have shown how such data can be used to identify novel genetic interactions, establish variant functional assays, and develop tests of phenotypic reversibility.…”

MCF2 is linked to a complex perisylvian syndrome and affects cortical lamination

“…The use of animal models is a powerful tool in order to mechanistically understand neurodevelopmental disorders 18 in the context of rare genetic variants associated with complex traits 19 . The in vivo model used in the present study allowed us to identify an interesting pathophysiological process caused by the acute KD of Mcf2 in the developing mouse.…”

Neurocognitive and Perceptual Processing in Genetic Mouse Models of Schizophrenia: Emerging Lessons

“…These studies revealed a contribution of a combination of low-penetrance common DNA variants and more penetrant and damaging mutations in single genes or blocks of adjacent genes (copy number variants [CNVs]). An effective approach toward elucidating underlying disease mechanisms would be to focus on the human mutations with large effect sizes to generate transgenic animal models that bear the exact same mutation through advanced genetic engineering approaches (Arguello and Gogos 2012; Mitchell and others 2011) (see Box 1). However, only a few such mutations have been unequivocally identified (Marshall and others 2017; Singh and others 2016; Takata and others 2014).…”