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Behavioral phenotypes of Disc1 missense mutations in mice

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http://www.cell.com/neuron/retrieve/pii/S0896627307002942
Original languageEnglish
Pages (from-to)387-402
Number of pages16
JournalNeuron
Volume54
Issue number3
DOIs
Publication statusPublished - 2007

Abstract

To support the role of DISC1 in human psychiatric disorders, we identified and analyzed two independently derived ENU-induced mutations in Exon 2 of mouse Disc1. Mice with mutation Q31L showed depressive-like behavior with deficits in the forced swim test and other measures that were reversed by the antidepressant bupropion, but not by rolipram, a phosphodiesterase-4 (PDE4) inhibitor. In contrast, L100P mutant mice exhibited schizophrenic-like behavior, with profound deficits in prepulse inhibition and latent inhibition that were reversed by antipsychotic treatment. Both mutant DISC1 proteins exhibited reduced binding to the known DISC1 binding partner PDE4B. Q31L mutants had lower PDE4B activity, consistent with their resistance to rolipram, suggesting decreased PDE4 activity as a contributory factor in depression. This study demonstrates that Disc1 missense mutations in mice give rise to phenotypes related to depression and schizophrenia, thus supporting the role of DISC1 in major mental illness.

    Research areas

  • 3',5'-Cyclic-AMP Phosphodiesterases/metabolism Alanine/genetics Animals Behavior, Animal/drug effects/*physiology Brain/anatomy & histology Cyclic Nucleotide Phosphodiesterases, Type 4 DNA Mutational Analysis/methods Female Glutamine/genetics Humans Leucine/genetics Male Mice Mice, Inbred C57BL Mice, Mutant Strains/anatomy & histology/*physiology Mutation, Missense/*genetics Nerve Tissue Proteins/*genetics Neural Inhibition/genetics *Phenotype Protein Binding/genetics Reflex, Acoustic/genetics Subcellular Fractions/metabolism Threonine/genetics

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