Behavioral phenotypes of Disc1 missense mutations in mice

被引:403
作者
Clapcote, Steven J.
Lipina, Tatiana V.
Millar, J. Kirsty
Mackie, Shaun
Christie, Sheila
Ogawa, Fumiaki
Lerch, Jason P.
Trimble, Keith
Uchiyama, Masashi
Sakuraba, Yoshiyuki
Kaneda, Hideki
Shiroishi, Toshihiko
Houslay, Miles D.
Henkelman, R. Mark
Sled, John G.
Gondo, Yoichi
Porteous, David J.
Roder, John C.
机构
[1] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada
[2] Univ Edinburgh, Med Genet Sect, Ctr Mol Med, Edinburgh EH4 2XU, Midlothian, Scotland
[3] Hosp Sick Children, Mouse Imaging Ctr, Toronto, ON M5G 1X8, Canada
[4] Hosp Sick Children, Auditory Sci Lab, Toronto, ON M5G 1X8, Canada
[5] RIKEN, Genom Sci Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan
[6] Univ Glasgow, IBLS, Mol Pharmacol Grp, Div Biochem & Mol Biol, Glasgow G12 8QQ, Lanark, Scotland
[7] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A1, Canada
[8] Univ Toronto, Dept Mol & Med Genet, Toronto, ON M5S 1A1, Canada
基金
英国医学研究理事会;
关键词
D O I
10.1016/j.neuron.2007.04.015
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:387 / 402
页数:16
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