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DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

14 November 2007. The relationship between schizophrenia and neurodevelopment may have just gotten stronger. In this week’s PNAS, researchers in the United States and Finland, led by Alcino Silva and Tyrone Cannon, University of California, Los Angeles, report that an inducible, reversible DISC1 C-terminal fragment, which is believed to mimic the effects of a mutation found in some families with schizophrenia and other psychiatric disorders, causes schizophrenia-like symptoms when turned on in young but not in adult mice. The findings suggest that disruption to DISC1 during brain development may contribute to disease pathology.

DISC1 was originally discovered when a translocation in the gene was linked to an extended Scottish family with increased risk for mental illness, particularly schizophrenia and bipolar disorder (see Millar et al., 2000). Since then, DISC1 has been a focus for researchers and has led to several mouse models of disease. What is interesting about this new model is that the gene can be turned on and off at will simply by adding or removing an inducer—the estrogen analog tamoxifen.

First author Weidong Li and colleagues coupled a DNA fragment coding the C-terminal fragment of DISC1 (amino acids 671-852) to a piece of DNA that codes for a mutant estrogen receptor ligand binding domain (LBD) that binds tamoxifen but not estrogen. The chimeric protein is normally silenced by chaperone proteins, but on addition of tamoxifen the LBD undergoes a conformational change that frees it from the chaperones. Once the construct was established in transgenic mice, the researchers were able to “turn on” the DISC1 fragment by simply giving the animals the estrogen analog.

Li and colleagues confirmed by Western blot analysis that the transgene, under the control of the neuronal α-calmodulin kinase II promoter, was expressed in the brain (cortex, hippocampus, striatum, and cerebellum). They also confirmed that the mice appeared and behaved normally—in the absence of tamoxifen. When the drug was administered, however, the animals’ behavior changed.

The researchers found that when the transgene was turned on at postnatal day 7, the animals exhibited behavioral deficits that have correlates in patients with schizophrenia. They had spatial working memory deficits (more frequently made incorrect choices in a delayed non-match to place task), showed symptoms of depression (gave up earlier in a forced swim test), and were asocial compared to wild-type mice (showed less interest in sniffing out a new mouse introduced into the same chamber). Interestingly, delaying administration of tamoxifen until the mice reached adulthood spared them from these deficits.

Bringing in Nudel and Lis1
How can this C-terminal fragment of DISC1 induce such profound behavioral changes? The researchers believe that the fragment binds to DISC1 partners, such as Nudel and Lis1 (see SRF related news story), preventing them from interacting with the full-length, functional DISC1. This type of dominant-negative effect has been proposed to explain human DISC1 effects and has served as the basis for a transgenic mouse model recently described by Akira Sawa and colleagues at Johns Hopkins University, Baltimore, Maryland (see SRF related news story).

To test this dominant-negative theory, Li and colleagues immunoprecipitated the chimeric protein and tested for the presence of Nudel and Lis1. They found that the chimera did, indeed, bind these proteins, which lends some credence to the idea. Furthermore, the researchers found that turning on the transgene led to morphological and functional changes in the brain, which is in keeping with interfering with Nudel and Lis1, proteins that play important roles in neurodevelopment. Li and colleagues found that animals given tamoxifen at postnatal day 7 had reduced dendritic complexity in that the number of branch points and intersections in hippocampal neurons was reduced. Hippocampal slices also exhibited reduced baseline neurotransmission, though long-term potentiation appeared to be unaffected.

How does this model relate to the human condition? Collaborating with colleagues in Finland, the researchers found that a DISC1 haplotype previously linked to risk for schizophrenia, working memory problems, and reduced gray matter density (see Cannon et al., 2005) quadruples the likelihood that the carrier will have deficits in sociability. The authors conclude that their findings “proved a critical functional link between the histological ramifications of altered DISC1 and the reduced gray matter density in schizophrenia that is known to vary with genetic proximity to affected individuals in monozygotic and dizygotic twins discordant for this disorder and to be associated with schizophrenia-related haplotypes of DISC1."—Tom Fagan.

Reference:
Li W, Zhou Y, Jentsch JD, Brown RAM, Tian X, Ehninger D, Hennah W, Peltonen L, Lonnqvist J, Huttunen MO, Kaprio J, Trachtenberg JT, Silva AJ, Cannon TD. Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. PNAS. 2007 Nov 13;104:18280-18285. Abstract

 
Comments on News and Primary Papers
Comment by:  John Roder
Submitted 30 November 2007 Posted 30 November 2007

Some observations on the new report by Li and colleagues: this work is the first to map subregions of DISC1 and to show that a region that binds Nudel and LIS1 is important in generating schizophrenia-like perturbations in vivo. The authors express DISC1 C-terminus in mice, which interacts with Nudel and LIS1. They showed less native mouse DISC1 associations with Nudel mouse following gene induction. This suggests a dominant-negative mechanism.

No data was shown on native DISC1 levels following induction. Work from the Sawa lab shows that if murine DISC1 levels are reduced in non-engineered mice using RNAi, severe perturbations in development of nervous system are seen (Kamiya et al., 2005); however, behavior was not measured in this study. Severe perturbations would be expected based on the neonatal ventral hippocampal lesion model. In this latter model early brain lesions lead to later impairments in PPI and other behaviors consistent with schizophrenic-like behavior.

They use a promoter only expressed in the forebrain,...  Read more


View all comments by John Roder

Comment by:  Akira Sawa, SRF Advisor
Submitted 3 December 2007 Posted 3 December 2007

DISC1 may be a promising entry point to explore important disease pathways for schizophrenia and related mental conditions; thus, animal models that can provide us with insights into the pathways involving DISC1 may be helpful. In this sense, the new animal model reported by Li et al. (Silva and Cannon’s group at UCLA) has great significance in this field.

They made mice expressing a short domain of DISC1 that may block interaction of DISC1 with a set of protein interactors, including NUDEL/NDEL1 and LIS1. This approach, if the domain is much shorter, will be an important methodology in exploring the disease pathways based on protein interactions. Although the manuscript is excellent, and appropriate as the first report, the domain expressed in the transgenic mice can interact with more than 30-40 proteins, and the phenotypes that the authors observed might not be attributable to the disturbance of protein interactions of DISC1 and NUDEL or LIS1.

Now we have at least five different types of animal models for DISC1, all of which have unique advantages and...  Read more


View all comments by Akira Sawa

Comment by:  David J. Porteous, SRF Advisor
Submitted 21 December 2007 Posted 22 December 2007

On the DISC1 bus
You wait ages for a bus, then a string of them come one behind the other. First, Koike et al. (2006) reported that the 129 strain of mouse had a small detection of the DISC1 gene and this was associated with a deficit on a learning task. The interpretation of this observation was somewhat complicated by the subsequent recognition that the majority, if not all, major DISC1 isoforms are unaffected by the deletion, but this needs further work (Ishizuka et al., 2007). Then, Clapcote et al. (2007) provided a very detailed characterization of two independent ENU-induced mouse missense mutations of DISC1, showing selective brain shrinkage and marked behavioral abnormalities that in one mutant were schizophrenia-like, the other more akin to mood disorder. Importantly, these phenotypes could be differentially rescued by antipsychotics or antidepressants. The main finger pointed to disruption of the interaction with PDE4...  Read more


View all comments by David J. Porteous
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