The transcriptome landscape associated with Disrupted-in-Schizophrenia-1 locus impairment in early development and adulthood

SCHIZOPHRENIA RESEARCH

卷:210

Article

Yang, Kun¹  Kondo, Mari A.^1,7  Jaaro-Peled, Hanna¹  Cash-Padgett, Tyler¹  Kano, Shin-ichi^1,8  Ishizuka, Koko¹  Pevsner, Jonathan^2,5  Tomoda, Toshifumi⁶  Sawa, Akira^1,2,3,4  Niwa, Minae^1,8 

[1] Johns Hopkins Univ, Dept Psychiat, Sch Med, Baltimore, MD 21287 USA

[2] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA

[4] Johns Hopkins Univ, Sch Med, Dept Mental Hlth, Baltimore, MD 21205 USA

[5] Kennedy Krieger Inst, Baltimore, MD 21205 USA

[6] Kyoto Univ, Med Innovat Ctr, Kyoto 6068397, Japan

[7] Univ New South Wales, Sch Psychiat, Fac Med, Sydney, NSW 2052, Australia

[8] Univ Alabama Birmingham, Birmingham Sch Med, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35233 USA

关键词: DISC1;    Prefrontal cortex;    Neurodevelopment;    RNA sequencing;    Mouse model;   

DOI  :  10.1016/j.schres.2019.05.032

来源: Elsevier

【 摘 要 】

DISC1 was originally expected to be a genetic risk factor for schizophrenia, but the genome wide association studies have not supported this idea. In contrast, neurobiological studies of DISC1 in cell and animal models have demonstrated that direct perturbation of DISC1 protein elicits neurobiological and behavioral abnormalities relevant to a wide range of psychiatric conditions, in particular psychosis. Thus, the utility of DISC1 as a biological lead for psychosis research is clear. In the present study, we aimed to capture changes in the molecular landscape in the prefrontal cortex upon perturbation of DISC1, using the Disc1 locus impairment (Disc1-LI) model in which the majority of Disc1 isoforms have been depleted, and to explore potential molecular mediators relevant to psychiatric conditions. We observed a robust change in gene expression profile elicited by Disc1-LI in which the stronger effects on molecular networks were observed in early stage compared with those in adulthood. Significant alterations were found in specific pathways relevant to psychiatric conditions, such as pathways of signaling by G protein-coupled receptor, neurotransmitter release cycle, and voltage gated potassium channels. The differentially expressed genes (DEGs) between Disc1-LI and wild-type mice are significantly enriched not only in neurons, but also in astrocytes and oligodendrocyte precursor cells. The brain-disorder-associated genes at the mRNA and protein levels rather than those at the genomic levels are enriched in the DEGs. Together, our present study supports the utility of Disc1-LI mice in biological research for psychiatric disorder-associated molecular networks. (C) 2019 Published by Elsevier B.V.

【 授权许可】

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