Comparative analysis of cellular expression pattern of schizophrenia risk genes in human versus mouse cortex

Hai-Long Zhang,Jiuzhou Wang,Dong-Min Yin,Wei Han,Weichen Song,Guan Ning Lin,Jia-Wen Long

doi:10.1186/s13578-019-0352-5

Abstract

BackgroundSchizophrenia is a common psychiatric disease with high hereditary. The identification of schizophrenia risk genes (SRG) has shed light on its pathophysiological mechanisms. Mouse genetic models have been widely used to study the function of SRG in the brain with a cell type specific fashion. However, whether the cellular expression pattern of SRG is conserved between human and mouse brain is not thoroughly studied.ResultsWe analyzed the single-cell transcription of 180 SRG from human and mouse primary visual cortex (V1). We compared the percentage of glutamatergic, GABAergic and non-neuronal cells that express each SRG between mouse and human V1 cortex. Thirty percent (54/180) of SRG had significantly different expression rate in glutamatergic neurons between mouse and human V1 cortex. By contrast, only 5.6% (10/180) of SRG showed significantly different expression in GABAergic neurons, which is similar with the ratio of SRG (15/180) with species difference in total cell populations. Strikingly, the percentage of non-neuronal cells expressing all SRG are indistinguishable between human and mouse V1 cortex. We further analyzed the biological significance of differentially expressed SRG by gene ontology. The species-different SRG in glutamatergic neurons are highly expressed in dendrite and axon. They are enriched in the biological process of response to stimulus. However, the differentially expressed SRG in GABAergic neurons are enriched in the regulation of organelle organization.ConclusionGABAergic neurons are more conserved in the expression of SRG than glutamatergic neurons while the non-neuronal cells show the species conservation for the expression of all SRG. It should be cautious to use mouse models to study those SRG which show different cellular expression pattern between human and mouse cortex.

Highlights

Schizophrenia is a common psychiatric disease with high hereditary
We focused on the primary visual cortex (V1) because V1 is the only brain region where the single cell RNA-seq data is currently available for both human and mouse cortex in Allen Brain Institute
The number of schizophre‐ nia risk genes (SRG)-positive and SRG-negative cells in the population of glutamatergic neuron, GABAergic neuron and non-neuronal cell were listed in Additional file 1: Table S1

Summary

Introduction

Schizophrenia is a common psychiatric disease with high hereditary. The identification of schizophre‐ nia risk genes (SRG) has shed light on its pathophysiological mechanisms. Mouse genetic models have been widely used to study the function of SRG in the brain with a cell type specific fashion. Whether the cellular expres‐ sion pattern of SRG is conserved between human and mouse brain is not thoroughly studied. Using mouse models to study SZ have been challenged due to the species difference [6]. Human brain may be unique for some high-level functions which are affected in SZ (for example, cognition, decision, etc.) [7]. Efforts have been made to evaluate and decrease the difference between human and psychiatric mouse model in terms of behavioral assessment and pharmacology [8, 9]. The cellular expression pattern of SRG may have species difference in human versus mouse brain. A comprehensive assessment of species difference of SRG in cortex of human and mouse is still lacking

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Discussion

Conclusion