Pharmacogenomics and animal models of schizophrenia

Schizophrenia is a syndromal brain disease of largely unknown pathophysiology and most likely heterogeneous etiology in which genetic predisposition constitutes the major risk factor. In recent years, a shift from a monolithic view of the disorder is leading to its dissection into component phenotypic modules or endophenotypes that may differ in pathophysiology, underlying genetic diathesis, or treatment response. Reducing phenotypic heterogeneity by focusing on endophenotypes will facilitate the production of valid animal models to be used in experimental approaches, improve our chances of uncovering genes predisposing to the disease in linkage or association approaches, and simplify generation of novel molecular targets for the drug discovery process. We hereby review some recently generated mouse models that replicate specific endophenotypes observed in schizophrenia and that implicate putative contributing genes that may be exploited to explore novel drug targets. These are derived from opposing but complementary perspectives. One approach developed in our work begins with mouse models of schizophrenia traits to uncover candidate schizophrenia genes. Another approach followed by several other groups begins with putative schizophrenia vulnerability genes to investigate the corresponding endophenotype in mouse models. Combined with global analysis of gene expression, these mouse models offer the hope that the disease‐causing and treatment pathways implicated in schizophrenia will finally be unraveled. Drug Dev. Res. 60:95–103, 2003. © 2003 Wiley‐Liss, Inc.