SZ is a condition that impairs high brain functions, some of which are specific to humans, complicating modeling the disease in mice. How can we evaluate in mice the existence of hallucination, delusion, and disorganized speech, which are characteristics of schizophrenia? Thus, behavioral deficits observed in mouse models might not serve as sufficient criteria to judge whether they are good models for schizophrenia.
For the past decade, there has been enormous progress in understanding the neurobiology of schizophrenia.1
Major progress was made by identification of susceptibility genes for schizophrenia.2
Although causality is hard to prove, these genetic factors have shed light on specific biological cascades that are linked to the pathology of the disease.3
Another major advance in schizophrenia research is identification of structural and pathological alterations that are frequently found in brains of patients with schizophrenia: Enlarged ventricles at the gross anatomy level have been reported in many brain imaging studies4
; dendritic changes in the pyramidal neurons5
and alteration of specific subtypes of interneurons6
are known to be important in the pathology of schizophrenia.
Mouse models for other brain disorders, such as Alzheimer disease, have been validated by utilizing representative neuropathological hallmarks found in the brains from patients with these diseases.7
As a result, these models are accepted to be very useful for molecular understanding of the mechanisms and course of the disease, as well as promising for compound screening for translational purposes. Combined with the ability to modulate the etiology of disease directly by straightforward genetic engineering, mice provide a good resource for modeling brain disorders. In analogy to these successful cases, anatomical and neuropathological changes identified in brains of patients with schizophrenia may become good indicators to validate possible mouse models for schizophrenia.
Based on this notion, this review first summarizes anatomical and neuropathological changes in schizophrenia brains that have been reported in brain imaging and neuropathological studies. We then discuss how such hallmarks are studied in putative mouse models for schizophrenia. In this discussion, we will also overview neuropathological changes found in classic nongenetic rodent models for schizophrenia, although most of them have been generated in rats. Compared with nongenetic models, we will finally discuss how genetically engineered mice will be useful in studies of schizophrenia with both basic and translational significance. This review does not aim at covering all previous publications and models but instead proposes a useful strategy for mouse models for schizophrenia research.