[Abstract Title]. - Society for Neuroscience

254. Schizophrenia: Mutant Animal Models
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 254.17/Y6
Topic: C.15.d. Schizophrenia: Mutant animal models
Support: Stanley Medical Research Institute
Title: Comparison of distinct DISC1 animal models: roles for dopaminergic pathway and
thalamus
Authors: *H. JAARO-PELED 1 , S. TANKOU 1 , S. SESHADRI 1 , R. MURAI 4 , M. NIWA 4 , C.
A. FOSS 2 , T. HIKIDA 1 , M. GALLAGHER 3 , T. NABESHIMA 4 , M. G. POMPER 2 , A. SAWA 1 ;
1 Psychiatry, 2 Radiology, 3 Psychological and Brain Sci., Johns Hopkins Univ., Baltimore, MD;
4 Dept. of Chem. Pharmacol., Meijo Univ., Nagoya, Japan
Abstract: DISC1 is a major susceptibility factor for several neuropsychiatric diseases. The
DISC1 protein is expressed in the cerebral cortex and hippocampus, but also in the thalamus and
hypothalamus. Thus, it would be desirable to compare more than one DISC1 animal model to
explore its multiple roles in vivo. Here we compare two distinct DISC1 transgenic mouse
models. The first expresses a dominant-negative mutant DISC1 under the control of the
αCaMKII promoter (Hikida et al 2007, PNAS). The other expresses the same mutant under the
control of the prion protein (PrP) promoter. The αCaMKII promoter turns on the transgene
expression postnatally mainly in the forebrain pyramidal neurons, whereas the PrP promoter
activates the mutant DISC1 from E13 in several types of cells all over the brain. Both types of
transgenic mice display a hyperdopaminergic phenotype: hyperactivity especially following an
amphetamine challenge; increased binding of the dopamine D2 receptor antagonist raclopride to
the striatum in PET scan; and a prepulse inhibition deficit. These results support the notion that a
postnatal DISC1 disturbance in the cortex and hippocampus is associated with the classic
dopamine hypothesis of schizophrenia. The PrP promoter directed expression of dominatnegative
DISC1 is more similar to the endogenous DISC1 expression both temporally and
spatially, which might explain the stronger phenotype. Notably, in contrast to the αCaMKII
promoter-driven mutant DISC1, the endogenous DISC1 and the PrP promoter-driven mutant
DISC1 are strongly and broadly expressed in the thalamus and hypothalamus. We are currently
investigating potential behavioral consequences of disturbance of endogenous DISC1 in the
thalamus.
Disclosures: H. Jaaro-Peled , None; S. Tankou, None; S. Seshadri, None; R. Murai,
None; M. Niwa, None; C.A. Foss, None; T. Hikida, None; M. Gallagher, None; T.
Nabeshima, None; M.G. Pomper, None; A. Sawa, None.