Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1

Sanbing Shen, Bing Lang, Chizu Nakamoto, Feng Zhang, Jin Pu, Soh-Leh Kuan, Christina Chatzi, Shuisheng He, Iain Mackie, Nicholas J. Brandon, Karen L. Marquis, Mark Day, Orest Hurko, Colin D. McCaig, Gernot Riedel, David St Clair

Research output: Contribution to journalArticle

202 Citations (Scopus)

Abstract

Disrupted-in-Schizophrenia-1 (DISC1), identified by positional cloning of a balanced translocation (1; 11) with the breakpoint in intron 8 of a large Scottish pedigree, is associated with a range of neuropsychiatric disorders including schizophrenia. To model this mutation in mice, we have generated Disc1(tr) transgenic mice expressing 2 copies of truncated Disc1 encoding the first 8 exons using a bacterial artificial chromosome (BAC). With this partial simulation of the human situation, we have discovered a range of phenotypes including a series of novel features not previously reported. Disc1(tr) transgenic mice display enlarged lateral ventricles, reduced cerebral cortex, partial agenesis of the corpus callosum, and thinning of layers II/III with reduced neural proliferation at midneurogenesis. Parvalbumin GABAergic neurons are reduced in the hippocampus and medial prefrontal cortex, and displaced in the dorsolateral frontal cortex. In culture, transgenic neurons grow fewer and shorter neurites. Behaviorally, transgenic mice exhibit increased immobility and reduced vocalization in depression-related tests, and impairment in conditioning of latent inhibition. These abnormalities in Disc1(tr) transgenic mice are consistent with findings in severe schizophrenia.

Original languageEnglish
Pages (from-to)10893-10904
Number of pages12
JournalJournal of Neuroscience
Volume28
Issue number43
DOIs
Publication statusPublished - 22 Oct 2008

Keywords

  • Age Factors
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Behavior, Animal
  • Bromodeoxyuridine
  • Cells, Cultured
  • Cerebral Cortex
  • Disease Models, Animal
  • Embryo, Mammalian
  • Gene Expression Regulation
  • Green Fluorescent Proteins
  • Hindlimb Suspension
  • Inhibition (Psychology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Nerve Tissue Proteins
  • Neurites
  • Neurons
  • Parvalbumins
  • Phenotype
  • Schizophrenia
  • Swimming
  • bacterial artificial chromosome
  • behavior
  • Disc1
  • neuroanatomy
  • schizophrenia
  • transgenic mice

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  • Cite this

    Shen, S., Lang, B., Nakamoto, C., Zhang, F., Pu, J., Kuan, S-L., Chatzi, C., He, S., Mackie, I., Brandon, N. J., Marquis, K. L., Day, M., Hurko, O., McCaig, C. D., Riedel, G., & St Clair, D. (2008). Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1. Journal of Neuroscience, 28(43), 10893-10904. https://doi.org/10.1523/JNEUROSCI.3299-08.2008