Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice

doi:10.1073/pnas.0706900104

Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice

*Department of Neurobiology,
^†Semel Institute,
^‡Department of Psychology,
^§Brain Research Institute, and
^¶Department of Urology, University of California, Los Angeles, CA 90095; and
^‖Department of Molecular Medicine, Biomedicum, and
**Department of Mental Health and Alcohol Research, National Public Health Institute, 00251, Helsinki, Finland

Edited by Richard F. Thompson, University of Southern California, Los Angeles, CA, and approved September 14, 2007 (received for review July 23, 2007)

Abstract

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.

Footnotes

^††To whom correspondence should be addressed. E-mail: silvaa{at}mednet.ucla.edu
Author contributions: W.L. and A.J.S. designed research; W.L., Y.Z., X.T., and D.E. performed research; W.L. and J.T.T. contributed new reagents/analytic tools; W.L., Y.Z., R.A.M.B., W.H., L.P., J.L., M.O.H., J.K., and T.D.C. analyzed data; and W.L., J.D.J., R.A.M.B., A.J.S., and T.D.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0706900104/DC1.
Abbreviations:

DISC1,

disrupted-in-schizophrenia 1;

DISC1-cc,

DISC1 C-terminal fragment;

LBD,

ligand-binding domain;

ERa,

estrogen receptor a subunit;

DNMTP,

delayed nonmatched to place;

PLSD,

protected least significant difference;

tam,

tamoxifen;

LTP,

long-term potentiation;

fEPSP,

field excitatory postsynaptic potential;

I/O,

input/output.