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Annotation

Low NC, Hardy J. What is a schizophrenic mouse? Neuron . 2007 May 3 ; 54(3):348-9. PubMed Abstract

Comments on Paper and Primary News
Primary News: New Spin on DISC1—Mouse Mutation Impairs Behavior

Comment by:  Akira Sawa, SRF Advisor
Submitted 8 May 2007 Posted 8 May 2007

This is outstanding work reporting DISC1 genetically engineered mice. Thus far, one type of DISC1 mutant mouse has been reported, by Gogos and colleagues (Koike et al., 2006).

There are two remarkable points in this work. First, of most importance, John Roder and Steve Clapcote have been very successful in using mice with ENU-induced mutations for their questions. Due to the complexity of the DISC1 gene and isoforms, several groups, including ours, have tried but not succeeded in generating knockout mice. However, Roder and Clapcote found alternative mice that could be used in testing our main hypothesis. I believe that the majority of the success in this work is on this particular point. Indeed, to explore animal models for other susceptibility genes for major mental illnesses, this approach should be considered.

Second, it is very interesting that different mutations in the same gene display different types of phenotypes. I appreciate the excellence in the extensive behavioral assays in this work.

Although we need...  Read more


View all comments by Akira Sawa

Primary News: New Spin on DISC1—Mouse Mutation Impairs Behavior

Comment by:  Christopher Ross
Submitted 8 May 2007 Posted 8 May 2007

This paper demonstrates that mutations in DISC1 can alter mouse behavior, brain structure, and biochemistry, consistent with the idea that DISC1 is related to major psychiatric disorders. This is already an important result. But more strikingly, the authors’ interpretation is that one mutation (L100P) causes a phenotype similar to schizophrenia, while the other mutation (Q31L) results in a phenotype similar to affective disorder.

There are a number of caveats that need to be considered. No patients with equivalent mutations have been identified. The behavioral tests have only a hypothesized or empiric relevance to behavior in the human illnesses. DISC1 itself, while a very strong candidate gene, is still not fully validated, and the best evidence for its role in schizophrenia still arises from the single large pedigree in Scotland.

Despite these caveats, I believe this paper is potentially a major advance. The authors’ interpretations are provocative, and could have far-reaching implications for understanding of the biological bases of psychiatric diseases. The...  Read more


View all comments by Christopher Ross

Primary News: New Spin on DISC1—Mouse Mutation Impairs Behavior

Comment by:  Nick Brandon (Disclosure)
Submitted 8 May 2007 Posted 8 May 2007

Mutant Mice Bring Further Excitement to the DISC1-PDE4 Arena
DISC1 continues to ride a wave of optimism as we look for real breakthroughs in the molecular events underlying major psychiatric disorders including schizophrenia, bipolar, and depression. In 2005, its fortunes became entwined with those of the phosphodiesterase PDE4B as they were shown to functionally and physically interact (Millar et al., 2005). Evidence linking PDE4B to depression has been known for some time, but in the wake of the DISC1 finding, its link to schizophrenia has hardened (Siuciak et al., 2007; Menniti et al., 2006; Pickard et al., 2007).

The Roder and Porteous labs have come together to produce a fantastic paper describing two ENU mutant mice lines with specific mutations in the N-terminus of DISC1. Luck was on their side as the mutations seem to have a direct impact on the interaction with the PDE4B. Furthermore, the two lines look to have...  Read more


View all comments by Nick Brandon
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