Mutant mouse models in evaluating novel approaches to antipsychotic treatment

In this review we consider the application of mutant mouse phenotypes to the study of psychotic illness in general and schizophrenia in particular, as they relate to behavioral, psychopharmacological, and cellular phenotypes of putative import for antipsychotic drug development. Mutant models appear to be heuristic at two main levels; firstly, by indicating the functional roles of neuronal components thought to be of relevance to the putative pathobiology of psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those neuronal components; secondly, by indicating the functional roles of genes associated with risk for psychotic illness, they help resolve overt behavioral and underlying cellular processes regulated by those risk genes. We focus initially on models of dopaminergic and glutamatergic dysfunction. Then, we consider advances in the genetics of schizophrenia and mutant models relating to replicable risk genes. Lastly, we extend this discussion by exemplifying two new variant approaches in mutant mice that may serve as prototypes for advancing antipsychotic drug development. There is continuing need not only to address numerous technical challenges but also to develop more “real-world” paradigms that reflect the milieu of gene × environment and gene × gene interactions that characterize psychotic illness and its response to antipsychotic drugs

Modeling schizophrenia: uncovering novel therapeutic targets

The vague relationship between diagnosis, underlying etiology and a rudimentary understanding of the pathophysiology of psychosis, particularly schizophrenia, has made it difficult to develop and validate suitable disease models for such disorders. Despite recent technological advancements, animal models have yet to yield a revolutionary treatment for schizophrenia. Refinement and standardization of assessment methods in the preclinical domain and streamlining of concepts from which animal models are generated are required, particularly in relation to models that recapitulate cognitive and negative symptoms of schizophrenia. In this review, caveats of current treatments for schizophrenia and current animal modeling strategies are examined in the context of their validity and potential for discovery of novel therapies, and finally, future prospects for the field are considered

Catechol-O-methyl transferase as a drug target for schizophrenia

Current antipsychotic drugs lack material efficacy against the negative symptoms and cognitive deficits of schizophrenia. There is considerable uncertainty regarding the optimal pharmacotherapeutic strategy for treating these and other aspects of psychotic illness. The present review summarises clinical, mutant, and psychopharmacological data related to catechol-O-methyltransferase (COMT), an enzyme involved in the catabolism of catecholamine neurotransmitters, with a view to establishing the antipsychotic potential of compounds targeting the action of this enzyme. The review examines clinical and preclinical genetic data linking COMT gene variation with risk for schizophrenia or specific symptoms or disease endophenotypes. We then summarise data concerning the behavioural effects of COMT inhibitors. These genetic and pharmacological data relating to COMT as a therapeutic target have implications for the development of individualised treatments for treatment-resistant symptoms of schizophrenia, including cognitive dysfunction and, potentially, negative symptoms

Susceptibility genes for schizophrenia: mutant models, endophenotypes and psychobiology

Schizophrenia is characterised by a multifactorial aetiology that involves genetic liability interacting with epigenetic and environmental factors to increase risk for developing the disorder. A consensus view is that the genetic component involves several common risk alleles of small effect and/or rare but penetrant copy number variations. Furthermore, there is increasing evidence for broader, overlapping genetic-phenotypic relationships in psychosis; for example, the same susceptibility genes also confer risk for bipolar disorder. Phenotypic characterisation of genetic models of candidate risk genes and/or putative pathophysiological processes implicated in schizophrenia, as well as examination of epidemiologically relevant gene × environment interactions in these models, can illuminate molecular and pathobiological mechanisms involved in schizophrenia. The present chapter outlines both the evidence from phenotypic studies in mutant mouse models related to schizophrenia and recently described mutant models addressing such gene × environment interactions. Emphasis is placed on evaluating the extent to which mutant phenotypes recapitulate the totality of the disease phenotype or model selective endophenotypes. We also discuss new developments and trends in relation to the functional genomics of psychosis which might help to inform on the construct validity of mutant models of schizophrenia and highlight methodological challenges in phenotypic evaluation that relate to such models

Physiological and behavioural responsivity to stress and anxiogenic stimuli in COMT-deficient mice

Catechol-O-methyltransferase, an enzyme involved in regulating brain catecholamine levels, has been implicated in anxiety, pain and/or stress responsivity. Elements of this putative association remain unclarified, notably whether: (a) COMT variation modulates responses to acute and/or chronic stress equally; (b) acute pharmacological inhibition of COMT produces comparable effects on anxiety to that observed after deletion of the COMT gene; (c) COMT genotype modulates action of anxiolytic drugs.<p></p> We aimed to further investigate the relationship between reduced COMT function, anxiety and stress responsivity in mice.<p></p> To compare the effect of acute vs. chronic restraint stress in female COMT KO vs. WT mice, serum corticosterone and cytokine concentrations were measured [Experiment 1]. Sensitivity to the benzodiazepines midazolam and chlordiazepoxide in the light–dark test was assessed in female COMT KO vs. WT mice [Experiment 2]. Effects of acute administration of the COMT inhibitor tolcapone, and of these same benzodiazepines thereon, in the light–dark test were assessed in female C57BL/6 mice [Experiment 3].<p></p> COMT KO mice demonstrated an increased corticosterone response to acute but not chronic stress, and a modified cytokine profile after chronic, but not acute stress. COMT KO mice showed increased anxiety, but benzodiazepine sensitivity was affected by COMT genotype. Whilst tolcapone had no effect on light/dark performance in C57BL6/J mice it decreased benzodiazepine sensitivity.<p></p> These data elaborate earlier findings of increased anxiety in female COMT KO mice and also clarify a role for COMT in modulating stress-related hormonal and immune parameters in a manner that depends on chronicity of the stressor

Molecular genetic models related to schizophrenia and psychotic illness: heuristics and challenges

Schizophrenia is a heritable disorder that may involve several common genes of small effect and/or rare copy number variation, with phenotypic heterogeneity across patients. Furthermore, any boundaries vis-à-vis other psychotic disorders are far from clear. Consequently, identification of informative animal models for this disorder, which typically relate to pharmacological and putative pathophysiological processes of uncertain validity, faces considerable challenges. In juxtaposition, the majority of mutant models for schizophrenia relate to the functional roles of a diverse set of genes associated with risk for the disorder or with such putative pathophysiological processes. This chapter seeks to outline the evidence from phenotypic studies in mutant models related to schizophrenia. These have commonly assessed the degree to which mutation of a schizophrenia-related gene is associated with the expression of several aspects of the schizophrenia phenotype or more circumscribed, schizophrenia-related endophenotypes; typically, they place specific emphasis on positive and negative symptoms and cognitive deficits, and extend to structural and other pathological features. We first consider the primary technological approaches to the generation of such mutants, to include their relative merits and demerits, and then highlight the diverse phenotypic approaches that have been developed for their assessment. The chapter then considers the application of mutant phenotypes to study pathobiological and pharmacological mechanisms thought to be relevant for schizophrenia, particularly in terms of dopaminergic and glutamatergic dysfunction, and to an increasing range of candidate susceptibility genes and copy number variants. Finally, we discuss several pertinent issues and challenges within the field which relate to both phenotypic evaluation and a growing appreciation of the functional genomics of schizophrenia and the involvement of gene × environment interactions