Detection of an immature dentate gyrus feature in human schizophrenia/bipolar patients

N M Walton,S Miyake,A K Gross,Y Zhou,R Shin,C L Heusner,Q Chen,K Tamura,K Tajinda,M Webster,J H Kogan,T Miyakawa,M Matsumoto

doi:10.1038/tp.2012.56

Abstract

Hippocampus-associated cognitive impairments are a common, highly conserved symptom of both schizophrenia (SCZ) and bipolar disorder (BPD). Although the hippocampus is likely an impacted region in SCZ/BPD patients, the molecular and cellular underpinnings of these impairments are difficult to identify. An emerging class of mouse models for these psychiatric diseases display similar cognitive impairments to those observed in human patients. The hippocampi of these mice possess a conserved pathophysiological alteration; we term the ‘immature dentate gyrus' (iDG), characterized by increased numbers of calretinin-positive immature neuronal progenitors, a dearth of calbindin-positive mature neurons and (often) constitutively increased neurogenesis. Although these models provide a link between cellular dysfunction and behavioral alteration, limited translational validity exists linking the iDG to human pathophysiology. In this study, we report the initial identification of an iDG-like phenotype in the hippocampi of human SCZ/BPD patients. These findings suggest a new motif for the etiology of these diseases and link an emerging class of mouse models to the human disease condition.

Highlights

Difficulties in understanding the etiology and mechanisms of schizophrenia (SCZ), and bipolar disorder (BPD) have been long-standing obstacles in the development of new therapeutics
It is widely believed that molecular and cellular changes to this region of the brain contribute to SCZ/BPD etiology. Following this line of reasoning, we sought to identify a conserved, recurring motif in the hippocampus of rodent models based on the identification of comparable cognitive deficits to those appreciated in SCZ/BPD patients
Comparative analysis of the hippocampi of CaMKIIa-hKO to controls confirmed the iDG molecular phenotype: Calretinin expression was significantly increased in CaMKIIa-hKO mice (Figures 1a and b; Doublecortin expression was significantly increased, data not shown), whereas the mature neuronal marker calbindin was significantly reduced in mutant mice (Figures 1c and d)

Summary

Introduction

Difficulties in understanding the etiology and mechanisms of schizophrenia (SCZ), and bipolar disorder (BPD) have been long-standing obstacles in the development of new therapeutics. SCZ and BPD have distinct clinical criteria for diagnosis, these diseases display significant overlap in symptoms.[2] In particular, SCZ and BPD patients share cognitive deficits, many of which have been linked to altered or impaired hippocampal function.[3] As such, it is widely believed that molecular and cellular changes to this region of the brain contribute to SCZ/BPD etiology Following this line of reasoning, we sought to identify a conserved, recurring motif in the hippocampus of rodent models based on the identification of comparable cognitive deficits to those appreciated in SCZ/BPD patients We were able to identify four independent strains whose behavioral profile warranted pathophysiological investigation of the brain

Methods

Results

Conclusion