Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice.
Disrupted-in-schizophrenia 1 (DISC1) was initially discovered through a balanced translocation (1;11)(q42.1;q14.3) that results in loss of the C terminus of the DISC1 protein, a region that is thought to play an important role in brain development. Here, we use an inducible and reversible transgenic system to demonstrate that early postnatal, but not adult induction, of a C-terminal portion of DISC1 in mice results in a cluster of schizophrenia-related phenotypes, including reduced hippocampal dendritic complexity, depressive-like traits, abnormal spatial working memory, and reduced sociability. Accordingly, we report that individuals in a discordant twin sample with a DISC1 haplotype, associating with schizophrenia as well as working memory impairments and reduced gray matter density, were more likely to show deficits in sociability than those without the haplotype. Our findings demonstrate that alterations in DISC1 function during brain development contribute to schizophrenia pathogenesis.
Li
Weidong
W
Department of Neurobiology, Semel Institute, Brain Research Institute, and Department of Urology, University of California, Los Angeles, CA 90095, USA.
Zhou
Yu
Y
Jentsch
J David
JD
Brown
Robert A M
RA
Tian
Xiaoli
X
Ehninger
Dan
D
Hennah
William
W
Peltonen
Leena
L
Lönnqvist
Jouko
J
Huttunen
Matti O
MO
Kaprio
Jaakko
J
Trachtenberg
Joshua T
JT
Silva
Alcino J
AJ
Cannon
Tyrone D
TD
D000818:Animals; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D010641:Phenotype
C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins