Review of pathological hallmarks of schizophrenia: comparison of genetic models with patients and nongenetic models

Abstract

Schizophrenia is a condition that impairs higher brain functions, some of which are specific to humans. After identification of susceptibility genes for schizophrenia, many efforts have been made to generate genetics-based models for the disease. It is under debate whether behavioral deficits observed in rodents are sufficient to characterize these models. Alternatively, anatomical and neuropathological changes identified in brains of patients with schizophrenia may be utilized as translatable characteristics between humans and rodents, which are important for validation of the models. Here, we overview such anatomical and neuropathological changes in humans: enlarged ventricles, dendritic changes in the pyramidal neurons, and alteration of specific subtypes of interneurons. In this review, we will overview such morphological changes in brains from patients with schizophrenia. Then, we will describe that some of these alterations are already recapitulated even in classic nongenetic models for schizophrenia. Finally, in comparison with the changes in patients and nongenetic models, we will discuss the anatomical and neuropathological manifestation in genetic models for schizophrenia.

Fig. 1.

In Vivo Magnetic Resonance Imaging Demonstrating Enlarged Lateral Ventricles in Both Patients With Schizophrenia and Mouse Models for Schizophrenia. A, Schizophrenia patients: shrinkage in the left temporal horn is detected (white arrow). B–D, mouse models for schizophrenia: a representative 2-dimensional image with the lateral ventricles (top in B) and a 3-dimensional construction (bottom in B). Enlarged lateral ventricles in transgenic mice expressing a truncated, dominant-negative form of DISC1 (C, conventional model in the C57 black strain; D, inducible model in a mixed genetic background). (A, reprinted with permission from The New England Journal of Medicine; 1992; B, top panel, and C, adapted from Proceedings of National Academy of Sciences United States of America; B, bottom panel, and D, reprinted by permission from Molecular Psychiatry; 2007.

Fig. 2.

Decrease in Dendritic Spine Density in Both (A) Patients With Schizophrenia (Prefrontal Cortex) and (B) A Mouse Model for Schizophrenia (Neuregulin-1 Type III Knockout Mice Compared With Wild-Type Animals in Hippocampus). (A, Adapted from Archives of General Psychiatry; 57:65–73; B, with permission from Chen et al Journal of Neuroscience; 2008).

Fig. 3.

Decrease in the Level of Parvalbumin (PV) Expression in the Prefrontal Cortex, Observed Both in (A) Schizophrenia Patients (mRNA Level) and (B) A Mouse Model for Schizophrenia (disrupted in schizophrenia-1 [DISC1] Transgenic Mice Expressing the Truncated, Dominant-Negative Form of “DISC1”). There was decrease in PV staining but not in calbindin (CB) staining. A, reprinted by permission from Nature Reviews Neuroscience; 2005. B, adapted from Proceedings of the National Academy of Sciences United States of America.