Modeling resilience to schizophrenia in genetically modified mice: a novel approach to drug discovery

Abstract

Complex psychiatric disorders, such as schizophrenia, arise from a combination of genetic, developmental, environmental and social factors. These vulnerabilities can be mitigated by adaptive factors in each of these domains engendering resilience. Modeling resilience in mice using transgenic approaches offers a direct path to intervention, as resilience mutations point directly to therapeutic targets. As prototypes for this approach, we discuss the three mouse models of schizophrenia resilience, all based on modulating glutamatergic synaptic transmission. This motivates the broader development of schizophrenia resilience mouse models independent of specific pathophysiological hypotheses as a strategy for drug discovery. Three guiding validation criteria are presented. A resilience-oriented approach should identify pharmacologically tractable targets and in turn offer new insights into pathophysiological mechanisms.

Keywords::

• antipsychotic
• behavioral testing
• d-amino acid oxidase
• glutaminase
• glycine transporter
• latent inhibition
• mouse model
• neurodevelopmental disorder
• prepulse inhibition
• serine

Financial & competing interests disclosure

The authors’ research on the GLS1 model has been supported by NIH grants K02-DA00356, R21-DA14055, P50-MH066171 and R01-MH087758, and NARSAD (S Rayport), and Israel Science Foundation Young Investigator grant 484/10 and Binational Science Foundation 2009301 (I Gaisler-Salomon). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.