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Mutant mouse models in evaluating novel approaches to antipsychotic treatment
Colm M P O'Tuathaigh1, Lieve Desbonnet, John L Waddington
1Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. c.otuathaigh@ucc.ie
Abstract:
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.
Insights
Mutant mouse models offer valuable insights into psychotic illnesses like schizophrenia by revealing neuronal functions and genetic risk factors. These models aid in understanding complex gene interactions crucial for antipsychotic drug development.
Area of Science:
- Neuroscience
- Psychiatry
- Pharmacology
Background:
- Psychotic illnesses, including schizophrenia, are complex disorders with poorly understood pathobiology.
- Developing effective antipsychotic drugs requires better models to study disease mechanisms and genetic risk factors.
Purpose of the Study:
- To review the application of mutant mouse phenotypes in studying psychotic illness and schizophrenia.
- To explore how these models inform behavioral, psychopharmacological, and cellular aspects relevant to antipsychotic drug development.
Main Methods:
- Focus on mutant mouse models of dopaminergic and glutamatergic dysfunction.
- Review advances in schizophrenia genetics and mutant models of risk genes.
- Exemplify novel variant approaches in mutant mice for drug development.
Main Results:
- Mutant models elucidate the functional roles of neuronal components in psychotic illness pathobiology.
- These models help resolve behavioral and cellular processes regulated by risk genes associated with psychotic illness.
- Specific models highlight dopaminergic and glutamatergic pathways and genetic risk factors.
Conclusions:
- Mutant mouse phenotypes are heuristic tools for understanding psychotic illness and schizophrenia.
- These models are crucial for identifying targets and developing novel antipsychotic medications.
- Future research needs more realistic paradigms to capture gene-environment and gene-gene interactions in psychotic disorders.
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