Modeling combined schizophrenia-related behavioral and metabolic phenotypes in rodents

• Metabolic abnormalities are present in first-onset schizophrenia.
• A schizophrenia model should encompass both behavioral and metabolic alterations.
• Diverse etiology can lead to shared behavioral and metabolic abnormalities.
• RDoC system can help the translational integration of animal models.

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.