Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, Lerch JP, Trimble K, Uchiyama M, Sakuraba Y, Kaneda H, Shiroishi T, Houslay MD, Henkelman RM, Sled JG, Gondo Y, Porteous DJ, Roder JC.
Behavioral phenotypes of Disc1 missense mutations in mice. Neuron.
2007 May 3
Comments on News and Primary Papers
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 to wait for any molecular and mechanistic analyses of these mice in the future, this work provides us outstanding methodologies in studying major mental conditions. I anticipate that four to five papers will come out in this year that report various types of DISC1 genetically engineered mice. Neutral comparison of all the DISC1 mice from different groups will provide important insights for DISC1 and its role in major mental conditions.
View all comments by Akira SawaComment 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 models provide strong support for further study of DISC1. DISC1 has numerous very interesting interacting proteins and thus may provide an entry into pathogenic pathways for psychiatric diseases. We have suggested that interactors at the centrosome, involved with neuronal development, may be especially relevant to schizophrenia, while interactors at the synapse, or related to signal transduction, may be especially relevant to affective disorder (Ross et al., 2006). The beginnings of an allelic series of DISC1 mutations will presage more detailed genotype-phenotype studies in a variety of mouse models, with potential relevance to both schizophrenia and affective disorder.
View all comments by Christopher RossComment 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 distinct phenotypes—one a little schizophrenic, the other depressive. It is known from the clinical and genetic data that DISC1 is associated with schizophrenia, bipolar, and MDD, so this mouse dichotomy is very intriguing.
The mutant line Q31L is claimed to have a “depressive-like” phenotype. This comes from behavioral experiments including a range of assays looking at depressive-like behaviors where this strain had severe deficits, treatable with the dual serotonin-noradrenaline reuptake inhibitor (SNRI) bupropion, commonly prescribed for depression. Together these findings could just as easily be linked to the negative symptoms of schizophrenia. Furthermore, Q31L also shows modest deficits in two sensory processing paradigms (latent inhibition and pre-pulse inhibition), for which antipsychotics had no impact, and a working memory deficit, so this strain has characteristics of all the three key domains of schizophrenia. The pharmacology gets more interesting when these animals are dosed with rolipram (PDE4 inhibitor, raises cAMP levels) and look to be resistant to its effects. At the protein level, while it effects no changes in absolute levels of DISC1 and PDE4B, it leads to a 50 percent reduction in PDE4 activity. This information connects together nicely with the rolipram resistance, and thus the authors suggest that elevated cAMP might explain the behaviors observed, but they unfortunately do not show any cAMP levels in these animals. The paper also reports a decreased binding of the mutant form of DISC1 with PDE4B in overexpressed systems; coupled with the decreased PDE activity, this is in slight contradiction to the original Millar paper (Millar et al., 2005), but as the authors explain, the complexity of the DISC1-PDE4 molecular partnership could easily explain this. From my perspective, the lack of data to date on DISC1-PDE4 brain complexes is a major weak point of this story—this needs to be addressed as we move forward. This will also allow us to understand better the role of different DISC1 isoforms.
L100P is the “schizophrenic” brother of Q31P and has severe deficits in two sensory processing paradigms (latent inhibition and pre-pulse inhibition) which is reversed by typical and atypical antipsychotic and rolipram. Rolipram is able to modulate the behavior as PDE4 activity levels are at a wild-type level. Again, it shows decreased levels of DISC1-PDE4 binding.
Together, these two lines, along with the Gogos mice and a further bank of DISC1 mice which we should expect to see in the next year, puts the field in a position where we are now able to start to dissect out the clearly complex biological functions of DISC1. But as I indicated earlier, we need more information on relevant DISC1 isoforms. We know from the DISC1 interactome that there are many exciting partnerships to develop, but we may not have the fortune of an ENU screen to pull out mice with specific effects on an interaction. The differences in the behavior and pharmacology of these two strains is striking. In combination with the impact on PDE4-DISC1 binding and PDE4 activity, it highlights how much still needs to be understood for this interaction alone. More immediately, the mice show clearly that specific DISC1 mutations may give rise to specific clinical end-points and open up DISC1 pharmacogenomics as a real possibility.
View all comments by Nick Brandon