Immature morphological properties in subcellular-scale structures in the dentate gyrus of Schnurri-2 knockout mice: a model for schizophrenia and intellectual disability

Akito Nakao,Shunsuke Ishii,Hideo Hagihara,Tsuyoshi Takagi,Koji Ohira,Nobuteru Usuda,Tsuyoshi Miyakawa,Kazuyoshi Murata,Naoyuki Miyazaki

doi:10.1186/s13041-017-0339-2

Abstract

Accumulating evidence suggests that subcellular-scale structures such as dendritic spine and mitochondria may be involved in the pathogenesis/pathophysiology of schizophrenia and intellectual disability. Previously, we proposed mice lacking Schnurri-2 (Shn2; also called major histocompatibility complex [MHC]-binding protein 2 [MBP-2], or human immunodeficiency virus type I enhancer binding protein 2 [HIVEP2]) as a schizophrenia and intellectual disability model with mild chronic inflammation. In the mutants’ brains, there are increases in C4b and C1q genes, which are considered to mediate synapse elimination during postnatal development. However, morphological properties of subcellular-scale structures such as dendritic spine in Shn2 knockout (KO) mice remain unknown. In this study, we conducted three-dimensional morphological analyses in subcellular-scale structures in dentate gyrus granule cells of Shn2 KO mice by serial block-face scanning electron microscopy. Shn2 KO mice showed immature dendritic spine morphology characterized by increases in spine length and decreases in spine diameter. There was a non-significant tendency toward decrease in spine density of Shn2 KO mice over wild-type mice, and spine volume was indistinguishable between genotypes. Shn2 KO mice exhibited a significant reduction in GluR1 expression and a nominally significant decrease in SV2 expression, while PSD95 expression had a non-significant tendency to decrease in Shn2 KO mice. There were significant decreases in dendrite diameter, nuclear volume, and the number of constricted mitochondria in the mutants. Additionally, neuronal density was elevated in Shn2 KO mice. These results suggest that Shn2 KO mice serve as a unique tool for investigating morphological abnormalities of subcellular-scale structures in schizophrenia, intellectual disability, and its related disorders.

Highlights

Accumulating evidence suggests that abnormalities in subcellular-scale structures such as dendritic spine and mitochondria may be involved in the pathogenesis/ pathophysiology of schizophrenia, bipolar disorder, autism spectrum disorder, and intellectual disability [1,2,3,4]
Immature dendritic spine morphology in dentate gyrus (DG) of Shn2 KO mice We evaluated the effects of deficiency of Shn2 on the morphology of dendrites in granule cells in the middle molecular layer of the dorsal DG using serial images obtained with serial block-facescanning electron microscopy (SBF-scanning electron microscopy (SEM)) (Additional file 1: Figure S1)
The results remained significant for expression levels of GluR1 in the outer, middle, and inner molecular layers of the DG in Shn2 KO mice, while the other expression differences did not survive (Fig. 3 and Additional file 1: Figure S4). These results demonstrated that Shn2 KO mice showed significantly decreased expression levels of GluR1 in the whole molecular layer, whereas there were nominally significant decreases in Synaptic vesicle 2 (SV2) and Postsynaptic density 95 (PSD95) in specific regions of the molecular layer in the DG of Shn2 KO mice

Summary

Introduction

Accumulating evidence suggests that abnormalities in subcellular-scale structures such as dendritic spine and mitochondria may be involved in the pathogenesis/ pathophysiology of schizophrenia, bipolar disorder, autism spectrum disorder, and intellectual disability [1,2,3,4]. Shn is expressed in several brain regions including the hippocampus, cortex, and cerebellum [10]. We have previously reported that Shn KO mice demonstrated mild, widespread brain inflammation characterized by the up-regulation of NF-κBresponsive genes and activation of astrocytes [20]. Shn KO mice demonstrated multiple schizophrenia-related phenotypes, including behavioral abnormalities that resemble those of schizophrenics, transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and glutamic acid decarboxylase 67 levels, increased theta power on electroencephalograms, and a thinner cortex [20]. It is of interest that the morphology of neuronal dendritic spines in Shn KO mice be investigated

Methods

Results

Conclusion