Behavioral phenotypes of Disc1 missense mutations in mice.
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.
Clapcote
Steven J
SJ
Samuel Lunenfeld Research Institute at Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. mail.steve@btinternet.com
Lipina
Tatiana V
TV
Millar
J Kirsty
JK
Mackie
Shaun
S
Christie
Sheila
S
Ogawa
Fumiaki
F
Lerch
Jason P
JP
Trimble
Keith
K
Uchiyama
Masashi
M
Sakuraba
Yoshiyuki
Y
Kaneda
Hideki
H
Shiroishi
Toshihiko
T
Houslay
Miles D
MD
Henkelman
R Mark
RM
Sled
John G
JG
Gondo
Yoichi
Y
Porteous
David J
DJ
Roder
John C
JC
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000409:Alanine / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000033:anatomy & histology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005973:Glutamine / Q000235:genetics; D006801:Humans; D007930:Leucine / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000033:anatomy & histology / Q000502:physiology*; D020125:Mutation, Missense / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009433:Neural Inhibition / Q000235:genetics; D010641:Phenotype; D011485:Protein Binding / Q000235:genetics; D012022:Reflex, Acoustic / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism; D013912:Threonine / Q000235:genetics
C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D005973:Glutamine; D013912:Threonine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; D007930:Leucine; D000409:Alanine