1 August 2007. Finding a small animal model that recapitulates the full pathology of any disease is a tall order. Doing it for schizophrenia may be even harder, given the heterogeneous nature of the symptoms and the difficulties of identifying a solid pathological etiology. But the growing list of candidate genes for schizophrenia is giving modelers some new material to mold. In this week’s PNAS online, researchers led by Akira Sawa at Johns Hopkins University, Baltimore, Maryland, describe a transgenic mouse model of schizophrenia based on the disrupted in schizophrenia 1 (DISC1) gene. The mice exhibit physiological and behavioral abnormalities that mimic some features of schizophrenia.
DISC1 is arguably one of the strongest genetic links to schizophrenia. The association was first discovered in an extended Scottish family, in which a chromosomal translocation interrupts the coding region and truncates the protein product of the DISC1 gene (see SRF related news story). Since then, researchers have delved deeper into the biology of DISC1 and its links to schizophrenia and other major psychiatric conditions, including depression and bipolar disorder (see SRF live discussion). Though this is not the first DISC1 mouse model, it is the first to use the human gene, and it is the first to address the dominant-negative theory of DISC1 toxicity: Sawa and colleagues have postulated that in people with the DISC1 disruption, the truncated protein forms a dimer with normal copies of the protein, preventing them from performing their usual function.
To mimic this dominant-negative mode of action, lead authors Takatoshi Hikida, Hanna Jaaro-Peled and colleagues introduced a construct containing the C-terminally truncated human DISC1 gene into C57BL/6 mice. They chose to drive expression of the construct by using the α calmodulin kinase II promoter, which is turned on in postnatal neurons. Using in situ hybridization, Hikida, Jaaro-Peled and colleagues showed that the human transgene was expressed preferentially in neonatal animals rather than adults, and that it was especially prominent in the pyramidal neurons in the prefrontal cortex and the granule neurons in the dentate gyrus of the hippocampus, both anatomical areas of particular interest to schizophrenia researchers.
The animals seem to mimic schizophrenia phenotypes in several respects. Anatomically, the transgenic mice have enlarged brain ventricles in early adulthood (at 6 weeks of age). Enlargement of lateral ventricles is a common, though by no means consistent finding in schizophrenia patients. It is unclear what causes the ventricle enlargement in the mice, but the authors suggest that it does not appear to be due to neurodegeneration because by the time the animals reach 3 months, ventricular sizes are normal. The ventricular enlargement was asymmetrical, with a greater increase in the left hemisphere, and may be related to asymmetrical changes in brain regions, which have also been reported in schizophrenia. In the transgenic mice, the ratio of left to right hippocampal volume was lower than in normal mice. The authors also found a slight, though significant reduction in parvalbumin-containing neurons in the transgenic mice. Parvalbumin-positive interneurons have been reported to be selectively affected by schizophrenia (Lewis et al., 2005) and are thought to modulate γ-band brain waves, which are often disrupted in schizophrenia (see SRF related news story).
Behaviorally, the animals had a slight reduction in prepulse inhibition at 74 decibels. Prepulse inhibition, where a quiet tone reduces startle elicited by a subsequent louder one, is compromised in a subset of schizophrenia patients. Although the animals appeared hyperactive in an open field test, they showed no signs of anxiety. In tests of working memory the mice performed as well as wild-type, though they did take longer to find food in a maze test, which may be due to a weakened sense of smell or even to lack of motivation, suggest the authors. In fact, in a forced swim test, the transgenic DISC1 mice were much more immobile than wild-type. This type of immobility is often a symptom of depression, though the authors also point out that it could also be due to anhedonia, or lack of interest in pleasure.
Other DISC1 mouse models have been reported. Joseph Gogos and colleagues at Columbia University, New York, have described a spontaneous mouse DISC1 mutation that yields a truncated protein, which is rapidly degraded. Compared to wild-type, these mice perform poorly in working memory tasks, though they do not seem to have any neurodevelopmental problems (see SRF related news story). Earlier this year, Stephen Clapcote and colleagues reported on two mouse DISC1 mutants generated by random mutagenesis. Both point mutations, one seemed to yield a more depressed mouse, while the other had more "schizophrenic-like" behavior, much of which could be “treated” by antipsychotic medication. In both cases the mice suffered from extensive brain volume loss, suggesting gross neurodevelopmental defects. Both mutations appear to be loss-of-function since the mutated proteins fail to bind as well as wild-type DISC1 to phosphodiesterase 4B, which may be a key DISC1 binding partner (see SRF related news story).
One of the strengths of this new transgenic model is that the authors managed to get the transgene working in the B6 line of mice, which have not proven very conducive to DISC1 modeling. Since the B6 line is the standard for many behavioral and psychiatric studies, having the DISC1 model in this mouse line eliminates potential strain-to-strain variations that might complicate interpretation of experimental results.
Sawa and colleagues note that the differences between the DISC1 transgenic mice and normal wild-type mice are subtle. But perhaps this is to be expected, given that schizophrenia itself is widely believed to be the culmination of a multitude of genetic and environmentally elicited changes. “Thus, we suggest that the present model has advantages for testing genetic epistatic effects, as well as gene-environmental interactions for major mental illness,” write the authors. They propose that cross-breeding these mice with other genetically engineered animals may bring us a better model of disease, as may introducing the animals to social or environmental stressors.—Tom Fagan.
Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue R, Andrade M, Tankou S, Mori S, Gallagher M, Ishizuka K, Pletnikov M, Kida S, Sawa A. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. PNAS early edition. 2007, July 30. Abstract