Animal Models of Schizophrenia

Abstract

Schizophrenia may well represent one of the most heterogenous mental disorders in human history. This heterogeneity encompasses (1) etiology; where numerous putative genetic and environmental factors may contribute to disease manifestation, (2) symptomatology; with symptoms characterized by group; positive – behaviors not normally present in healthy subjects (e.g. hallucinations), negative – reduced expression of normal behaviors (e.g. reduced joy), and cognitive – reduced cognitive capabilities separable from negative symptoms (e.g. impaired attention), and (3) individual response variation to treatment. The complexity of this uniquely human disorder has complicated the development of suitable animal models with which to assay putative therapeutics. Moreover, the development of animal models is further limited by a lack of positive controls because currently approved therapeutics only addresses psychotic symptoms, with minor negative symptom treatment. Despite these complexities however, many animal models of schizophrenia have been developed mainly focusing on modeling individual symptoms. Validation criteria have been established to assay the utility of these models, determining the (1) face, (2) predictive, (3) construct, and (4) etiological validities, as well as (5) reproducibility of each model. Many of these models have been created following the development of major hypotheses of schizophrenia, including the dopaminergic, glutamatergic, and neurodevelopmental hypotheses. The former two models have largely consisted of manipulating these neurotransmitter systems to produce behavioral abnormalities with some relevance to symptoms or putative etiology of schizophrenia. Given the serotonergic link to hallucinations and cholinergic link to attention, other models have manipulated these systems also. Finally, there has also been a drive toward creating mouse models of schizophrenia utilizing transgenic technology. Thus, there are opportunities to combine both environmental and genetic factors to create more suitable models of schizophrenia. More sophisticated animal tasks are also being created with which to ascertain whether these models produce behavioral abnormalities consistent with patients with schizophrenia. While animal models of schizophrenia continue to be developed, we must be cognizant that (1) validating these models are limited to the degree by which Clinicians can provide relevant information on the behavior of these patients, and (2) any putative treatments that are developed are also likely to be given with concurrent antipsychotic treatment. While our knowledge of this devastating disorder increases and our animal models and tasks with which to measure their behaviors become more sophisticated, caution must still be taken when validating these models to limit complications when introducing putative therapeutics to human trials.