Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans

Abstract

Here, we report generation and characterization of Disrupted-In-Schizophrenia-1 (DISC1) genetically engineered mice as a potential model for major mental illnesses, such as schizophrenia. DISC1 is a promising genetic risk factor for major mental illnesses. In this transgenic model, a dominant-negative form of DISC1 (DN-DISC1) is expressed under the alphaCaMKII promoter. In vivo MRI of the DN-DISC1 mice detected enlarged lateral ventricles particularly on the left side, suggesting a link to the asymmetrical change in anatomy found in brains of patients with schizophrenia. Furthermore, selective reduction in the immunoreactivity of parvalbumin in the cortex, a marker for an interneuron deficit that may underlie cortical asynchrony, is observed in the DN-DISC1 mice. These results suggest that these transgenic mice may be used as a model for schizophrenia. DN-DISC1 mice also display several behavioral abnormalities, including hyperactivity, disturbance in sensorimotor gating and olfactory-associated behavior, and an anhedonia/depression-like deficit.

Fig. 1.

Production of DN-DISC1 tg mice. (a) Transgene construct. cDNA of DN-DISC1 was inserted into a modified pMM403 vector under the αCaMKII promoter. (b) DN-DISC1 transgene mRNA expression at the age of 2 months was assessed by RT-PCR. It was expressed in both tg lines in the following areas: OB, olfactory bulbs; FC, frontal cortex; Hp, hippocampus; BG, basal ganglia. (c) In situ hybridization on medial prefrontal cortex (mPFC) and hippocampus of tg line 37 at postnatal day 7 (P7) and at 3 months old (adult). AS, antisense probe; S, sense probe.

Fig. 2.

Anatomical changes of DN-DISC1 tg mice detected by MRI scans. (a) In vivo MRI scans. (Left) Lateral ventricles (LV) are enlarged in tg (n = 8) in comparison with wt (n = 7) (line 10, 6 weeks old) (*, F_(1,13) = 7.70, P = 0.016). (Center) The ratio of the LV to the whole brain volume (WBV) is increased in tg (*, F_(1,13) = 6.83, P = 0.022). (Right) A representative two-dimensional image (Upper) and a three-dimensional construction (Lower). (b) Left/right lateral ventricle volume ratio between tg (n = 7) and wt (n = 4) (#, suggestive at P = 0.057). (c) Ex vivo imaging. Ratio of left/right areas is significantly changed in hippocampus (Hp), but not in lateral cortex (Ctx) and basal ganglia (BG) between tg (n = 6) and wt (n = 6) (*, P < 0.05).

Fig. 3.

Immunostaining of interneurons in the medial prefrontal cortex. (a) (Left) High magnification representative pictures of staining patterns in the area marked in yellow in Right. (Right) Low magnification image demonstrating the area for the quantitative analyses, outlined in red. (b) Quantification of the staining. There was a significant reduction (**, P = 0.0059) in the number of parvalbumin (PV) cells in DN-DISC1 line 37 mice and no difference in calbindin (CB) or calretinin (CR) immunoreactivity.

Fig. 4.

Behavior assays. (a) tg mice are hyperactive. Results are shown for line 10 (line 37 behaved similarly). (Left) F_(1,17) = 4.94, P = 0.04. (Center) Divided to 4 × 30 min intervals. DN-DISC1 mice were significantly hyperactive during the second hour of the test (*, 60–90 min: F_(1,17) = 7.74, P = 0.013; 90–120 min: F_(1,17) = 5.4, P = 0.033) (Right) tg mice reared more than wt mice. (b) tg display impaired prepulse inhibition when the 120-dB pulse was preceded by a prepulse of 74 dB. There is a significant interaction between genotype and prepulse intensity [F_(4,68) = 5.18, P = 0.001]. (c) No significant difference between tg and wt in spatial working memory in a Y-maze paradigm, [F_(1,24) = 0.087, P = 0.77]. The dotted line indicates chance performance level. (d) It takes longer for tg to find hidden food pellet (*, P = 0.038). (e) tg mice were immobile significantly longer than their wt littermates. ANOVA: F_(1,20) = 8.66, P = 0.008.