[Abstract Title]. - Society for Neuroscience

Poster
254. Schizophrenia: Mutant Animal Models
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 254.18/Y7
Topic: C.15.d. Schizophrenia: Mutant animal models
Title: Prenatal expression of mutant human DISC1 determines schizophrenia-like alterations in
mice: support for neurodevelopmental hypothesis
Authors: Y. AYHAN 1 , O. NIKOLSKAIA 1 , S. BROWN 1 , M. VOGEL 2 , *C. A. ROSS 1 , M.
PLETNIKOV 1 ;
1 Div. Neurobiol, Johns Hopkins Med. Sch., Baltimore, MD; 2 MPRC, Univ. of Maryland,
Baltimore, MD
Abstract: Background: The Disrupted in Schizophrenia-1 (DISC-1) is a strong candidate gene in
the generation of major psychiatric disorders, first identified in a pedigree with a balanced
choromosomal translocation disrupting DISC1. The hypothetical product of the gene, mutant
human DISC1 can act as a dominant negative. Disruption of the normal gene function causes
abnormal neural migration and maturation during neurodevelopment. Although several DISC1
mouse models have been developed, the timing of the effects of mutant human DISC1
(mhDISC1) remains incompletely understood.
Methods: To evaluate the timing effects of mhDISC1, we used our Tet-off transgenic mouse
model of inducible expression of mhDISC1 restricted to forebrain areas. The expression of the
protein was regulated by feeding mice with doxycycline-containing food to generate three groups
of mice with expression of mhDISC1 prenatally and postnatally; prenatally only; or without
expression.
Results: Prenatal but not postnatal expression of mhDISC1 was associated with decreased
spontaneous alternation in Y maze, decreased social interaction and increased aggressiveness,
enhanced responses to a NMDA antagonist, MK-801, or amphetamine. In addition, prenatal but
not postnatal expression of the protein produced decreased cortical volume and increased
dendritic spine density in granule cells of the dentate gyrus. The effects of prenatal expression on
synaptic markers and DISC1 interactors are being evaluated and will be presented.
Conclusions: The results indicate that the prenatal expression of mhDISC1may determine its
schizophrenia-like phenotypic effects. Our findings provide a direct experimental support for the
neurodevelopmental hypothesis of schizophrenia and other psychiatric conditions.
Disclosures: Y. Ayhan, None; O. Nikolskaia, None; S. Brown, None; M. Vogel, None; C.A.
Ross , None; M. Pletnikov, None.