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Modeling combined schizophrenia-related behavioral and metabolic phenotypes in rodents
Zoltán Sarnyai1, Cassandra Jashar2, Berend Olivier3
1Discipline of Physiology and Pharmacology, James Cook University, Townsville, QLD, Australia; Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, QLD, Australia; Comparative Genome Centre, James Cook University, Townsville, QLD, Australia; Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University, Townsville, QLD, Australia.
Abstract:
Schizophrenia is a chronic, debilitating disorder with a complex behavioral and cognitive phenotype underlined by a similarly complex etiology involving an interaction between susceptibility genes and environmental factors during early development. Limited progress has been made in developing novel pharmacotherapy, partly due to a lack of valid animal models. The recent recognition of the potentially causal role of central and peripheral energy metabolism in the pathophysiology of schizophrenia raises the need of research on animal models that combine both behavioral and metabolic phenotypic domains, similar to what have been identified in humans. In this review we focus on selected genetic (DBA/2J mice, leptin receptor mutants, and PSD-93 knockout mice), early neurodevelopmental (maternal protein deprivation) and pharmacological (acute phencyclidine) animal models that capture the combined behavioral and metabolic abnormalities shown by schizophrenic patients. In reviewing behavioral phenotypes relevant to schizophrenia we apply the principles established by the Research Domain Criteria (RDoC) for better translation. We demonstrate that etiologically diverse manipulations such as specific breeding, deletion of genes that are primarily involved in metabolic regulation and in synaptic plasticity, as well as early metabolic deprivation and adult pharmacological challenge of the glutamate system can lead to schizophrenia-related behavioral and metabolic phenotypes, which suggest that these pathways might be interlinked. We propose that using animal models that combine different domains of schizophrenia can be used as a translationally valid approach to capture the system-level complex interplay between peripheral and central processes in the development of psychopathology.
Insights
Developing valid animal models for schizophrenia is crucial for advancing pharmacotherapy. This review highlights genetic, developmental, and pharmacological models that integrate behavioral and metabolic abnormalities, offering a translational approach to understanding schizophrenia.
Area of Science:
- Neuroscience
- Psychiatry
- Genetics
Background:
- Schizophrenia presents complex behavioral and cognitive symptoms with a multifaceted etiology involving genetic and environmental factors.
- Limited progress in pharmacotherapy is partly due to a lack of valid animal models that capture the disorder's complexity.
- Emerging evidence implicates central and peripheral energy metabolism in schizophrenia's pathophysiology, necessitating models with combined behavioral and metabolic phenotypes.
Purpose of the Study:
- To review animal models of schizophrenia that exhibit both behavioral and metabolic abnormalities.
- To assess the translational validity of these models for understanding schizophrenia's complex etiology.
- To explore the interconnections between metabolic and behavioral pathways in schizophrenia.
Main Methods:
- Focus on genetic models (DBA/2J mice, leptin receptor mutants, PSD-93 knockout mice).
- Include early neurodevelopmental models (maternal protein deprivation).
- Incorporate pharmacological models (acute phencyclidine administration).
- Utilize Research Domain Criteria (RDoC) principles for behavioral phenotype analysis.
Main Results:
- Diverse manipulations (genetic, developmental, pharmacological) induce schizophrenia-related behavioral and metabolic phenotypes.
- Specific genetic alterations, early metabolic deprivation, and glutamate system challenges result in combined abnormalities.
- These findings suggest interconnectedness between metabolic regulation, synaptic plasticity, and schizophrenia-related phenotypes.
Conclusions:
- Animal models integrating behavioral and metabolic domains offer a translationally valid approach to schizophrenia research.
- These models can capture the complex interplay between central and peripheral processes in psychopathology development.
- Further research using these comprehensive models is essential for advancing schizophrenia pharmacotherapy.
