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

Kun Yang, Mari A. Kondo, H. Jaaro-Peled, T. Cash-Padgett, Shin ichi Kano, Koko Ishizuka, Jonathan Pevsner, Toshifumi Tomoda, A. Sawa, M. Niwa

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)149-156
Number of pages8
JournalSchizophrenia Research
Volume210
DOIs
StatePublished - Aug 2019

Keywords

  • DISC1
  • Mouse model
  • Neurodevelopment
  • Prefrontal cortex
  • RNA sequencing

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Biological Psychiatry

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