Critical Reappraisal of Mechanistic Links of Copy Number Variants to Dimensional Constructs of Neuropsychiatric Disorders in Mouse Models

Abstract Copy number variants are deletions and duplications of a few thousand to million base pairs and are associated with extraordinarily high levels of autism spectrum disorder, schizophrenia, intellectual disability or attention‐deficit/hyperactivity disorder. The unprecedented levels of robust and reproducible penetrance of copy number variants make them one of the most promising and reliable entry points to delve into the mechanistic bases of many mental disorders. However, the precise mechanistic bases of these associations still remain elusive in humans due to the many genes encoded in each copy number variant and the diverse associated phenotypic features. Genetically engineered mice have provided a technical means to ascertain precise genetic mechanisms of association between copy number variants and dimensional aspects of mental illnesses. Molecular, cellular and neuronal phenotypes can be detected as potential mechanistic substrates for various behavioral constructs of mental illnesses. However, mouse models come with many technical pitfalls. Genetic background is not well controlled in many mouse models leading to rather obvious interpretative issues. Dose alterations of many copy number variants and single genes within copy number variants result in some molecular, cellular and neuronal phenotypes without a behavioral phenotype or with a behavioral phenotype opposite to what is seen in humans. In this review, I discuss technical and interpretative pitfalls of...
Source: Psychiatry and Clinical Neurosciences - Category: Neuroscience Authors: Tags: PCN Frontier Review Source Type: research