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Modeling Schizophrenia Phenotypes—DISC1 Transgenic Mouse Debuts

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

Comments on News and Primary Papers
Comment by:  David J. Porteous, SRF AdvisorKirsty Millar
Submitted 2 August 2007
Posted 2 August 2007

Several genetic studies point to involvement of DISC1 in major psychiatric illness, including schizophrenia and bipolar disorder, but to date the only causal variant that has been definitively identified is the translocation between human chromosomes 1 and 11 that co-segregates with major mental illness in a large Scottish family and which directly disrupts the DISC1 gene (Millar at al., 2000). It has been speculated that a truncated form of DISC1 may be expressed from the translocated allele and, if so, that this could exert a dominant-negative effect, but there is no such evidence from studies of the translocation cases. Rather, the evidence from studies of lymphoblastoid cell lines carrying the translocation suggests that haploinsufficiency is the most likely disease mechanism in this family (Millar et al., 2005). The unresolvable caveat to this, of course, is that it has not been possible to determine whether this is true also for the brain. Moreover, it is far from certain that any productive product from the translocation chromosome would be a perfectly truncated protein encoded by all the remaining exons, as opposed to an exon-skip isoform, with or without a hybrid protein component borrowing sequence information from chromosome 11. What does seem likely from other human studies is that additional genetic mechanisms, including missense mutations, altered expression, and possibly also copy number variation, play a role in the generality of DISC1 as a risk factor.

The evidence in support of DISC1 as an important biological determinant across a spectrum of major mental illness has now received a further boost from the study in PNAS by Hikida et al. The Sawa lab describes a transgenic approach where a truncated human DISC1 protein is expressed from a CAMKII promoter. The truncation was designed to mimic the hypothetical truncation arising from the Scottish translocation. This forebrain-specific promoter confers preferential expression of the transgene at neonatal stages, as distinct from the expression of the endogenous protein, which is abundant from embryonic development into adulthood. This model therefore permits investigation of the effect of the truncated protein in the forebrain within a specific developmental window, against a background of endogenous mouse DISC1 expression. Since there is no evidence for production of a truncated protein from the translocated allele, the relevance of this model to psychiatric illness remains unclear. However, on the positive side and from a functional perspective, dominant-negative effects as a consequence of expressing the truncated protein have already been demonstrated in cultured cells, altering the subcellular distribution of DISC1 and interaction with DISC1 partner proteins. Moreover, expression of the truncated form of DISC1 mimics downregulation of DISC1 in vivo, inhibiting migration of neurons in the developing mouse cortex (Kamiya et al., 2005). Thus, this model has the genuine potential to enhance our understanding of the biology of DISC1.

This is, in fact, the third study describing mice expressing modified DISC1 alleles. In the first study, Gogos and colleagues (Kioke et al., 2006) studied the effects of a modified DISC1 allele carrying a spontaneous 25 bp deletion in exon 6 that is present in all 129 mouse strains (Koike et al., 2007; see SRF related news story). This allele additionally has an artificial stop codon in exon 8 and a downstream polyadenylation signal. After back-crossing this mutagenised version of the 129 allele onto a C57Bl6 background, they reported a deficit in an assay of working memory in both heterozygous and homozygous mutants, but other standard behavioral tests were unaltered or unreported, and there were no anatomical, electrophysiological, or pharmacological studies included. In the second study, one led by the Roder laboratory, Toronto, we described two mouse strains with missense mutations in exon 2, Q31L and L100P (Clapcote et al., 2007). Reductions in brain volume, deficits in a range of standard behavioral tests, and responses to pharmacological treatments were reported, which can be summarized as consistent with the 100P mutants displaying schizophrenia-like phenotypes and the 31L mutants, mood disorder-like phenotypes. There is a frustrating dearth of consistent biomarkers for schizophrenia, but one of the best replicated findings is by brain imaging of enlarged ventricles in schizophrenia (also, but less markedly, in bipolar disorder). Adding to the observations of Clapcote et al., arguably the most striking claim by Hikida et al. is for altered ventricular brain volume and reduced brain laterality following neonatal transgenic overexpression of truncated DISC1. Additionally, behavioral tests were reported that overlap in part with those reported earlier by Clapcote et al. That three studies all describe behavioral abnormalities consistent with modeling components of schizophrenia is reassuring. That there are clear differences, too, between the phenotypes should come as no surprise either, given the important differences in terms of genetic lesion and developmental expression. Other mouse models are in the pipeline and they, too, will be welcomed. Indeed, this is very much what is needed for the field to move forward. But we should do so with some caution, paying careful attention to the specific nature of the models, what they can and cannot tell us about DISC1 biology, and what they may or may not tell us about the human condition. Although none of these models relates directly to a known causal variant, it appears that the mouse models concur with the human genetic studies in suggesting that there are likely to be several routes by which DISC1 can perturb brain function leading to characteristics of human mental illness. What we need now is for the human genetic studies to catch up with the mouse so that defined pathognomic variants can be modeled.

View all comments by David J. Porteous
View all comments by Kirsty MillarComment by:  John Roder
Submitted 2 August 2007
Posted 2 August 2007

A new mouse model from the Sawa lab strengthens the evidence for the candidate gene DISC1 playing a role in psychosis and mood disorders. This important paper is the first to address one potential disease mechanism, that of a dominant-negative effect. Expression of the C-terminal deletion of human DISC1—which represented the original rearrangement found by the Porteous group in the Scottish families with schizophrenia and depression—in transgenic mice driven by the α CaMKII promoter, first described by Mark Mayford when a postdoctoral fellow in the Kandel lab, leads to mice showing behaviors consistent with schizophrenia and depression, with enlarged lateral ventricles. Since the Sawa group expressed the human C-terminal truncation in mouse with no change in mouse DISC1 levels, they feel this supports a dominant-negative mechanism. More direct experiments are required. For example, create a null mutant mouse for DISC1 and express the full-length and truncated human DISC1 under the influence of their own promoter in transgenic mice using human BACs. Full-length human DISC1 would, hopefully, rescue the null. If so, then a mixture of full-length and truncated DISC1 proteins could be tried. No rescue by the mixture of full-length and truncated proteins would suggest a dominant-negative mechanism.

The Porteous group has shown no detectable DISC1 protein in lymphoblasts from the patients, and put forward the following implicit model. The C-terminal truncation of DISC1 makes the protein unstable and sensitive to degradation, a plausible alternative notion. In my opinion both are likely in different schizophrenia patients with perturbations in DISC1, most of which are alterations other than the C-terminal truncation. Some have SNPs that lead to as yet uncharacterized disease. It has been shown by the Sawa lab that mice with a partial RNAi knockdown of DISC1 show perturbations in brain development, and if aged to 8-12 weeks these mice might have shown behavioral and neuropathological hallmarks of schizophrenia and depression. There is currently no null mutation in the mouse that would address this issue, although DISC1 is one of the genes being targeted in the NIH knockout mouse project. Fortunately, there are now several mouse models—the more the better. The Gogos lab has a 25bp deletion in exon 6 that removes some, but not all isoforms. The Roder lab used a reverse genetic screen of an ENU archive to generate two missense mutants in non-conserved amino acids. The phenotypes of all these lines are nicely summarized in the Sawa paper. This work represents a step forward in our understanding of the DISC1 gene.

View all comments by John Roder

Comments on Related News

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Anil Malhotra, SRF Advisor
Submitted 21 November 2005
Posted 21 November 2005

The relationship between DISC1 and neuropsychiatric disorders, including schizophrenia, schizoaffective disorder, and bipolar disorder, has now been observed in several studies. Moreover, a number of studies have demonstrated that DISC1 appears to impact neurocognitive function. Nevertheless, the molecular mechanisms by which DISC1 could contribute to impaired CNS function are unclear, and these two papers shed light on this critical issue.

Millar et al. (2005) have followed the same strategy that they so successfully utilized in their initial DISC1 studies, identifying a translocation that associated with a psychotic illness. In contrast to DISC1, in which a pedigree was identified with a number of translocation carriers, this manuscript is based upon the identification of a single translocation carrier, who appears to manifest classic signs of schizophrenia, without evidence of mood dysregulation. Two genes are disrupted by this translocation: cadherin 8 and phosphodiesterase 4B (PDE4B). The researchers' elegant set of experiments provides compelling biological evidence that PDE4B interacts with DISC1 and suggests a mechanism mediated by cAMP for DISC1/PDE4B effects on basic molecular processes underlying learning, memory, and perhaps psychosis. It remains possible that PDE4B (and DISC1) are proteins fundamentally involved in cognitive processes, and that the observed relationship to psychotic illnesses represents a final common pathway of neurocognitive impairment. This would be consistent with data from our group (Lencz et al., in press) demonstrating that verbal memory impairment specifically predicts onset of psychosis in at-risk subjects. Similarly, Burdick et al. (2005) found that our DISC1 risk genotypes (Hodgkinson et al., 2004) were associated with impaired verbal working memory. Finally, Callicott et al. (2005) found that a DISC1 risk SNP, Ser704Cys, predicted hippocampal dysfunction, an SNP which we (DeRosse et al., unpublished data) have also found to link with the primary psychotic symptoms (persecutory delusions) manifested by the patient in the Millar et al. study. This body of evidence supports the notion that these proteins play fundamental roles in the key clinical manifestations of schizophrenia.

Kamiya et al. (2005) provide another potential mechanism for these effects, suggesting that a DISC1 mutation may disrupt cerebral cortical development, hinting that studies examining the role of DISC1 genotypes on brain structure and function in the at-risk schizophrenia pediatric patients may be fruitful.

Taken together, these papers add considerable new data suggesting that DISC1 plays a key role in the etiology of schizophrenia, and places DISC1 at the forefront of the rapidly growing body of schizophrenia candidate genes.

Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM, Goldman D, Malhotra AK. DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16(12):1399-1402. Abstract

Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 2005; 102(24): 8627-8632. Abstract

Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH, Malhotra AK. Disrupted in Schizophrenia (DISC1): Association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 2004; 75:862-872. Abstract

Lencz T, Smith CW, McLaughlin D, Auther A, Nakayama E, Hovey L, Cornblatt BA. Generalized and specific neurocognitive deficits in prodromal schizophrenia. Biological Psychiatry (in press).

View all comments by Anil Malhotra

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Comment by:  Angus Nairn
Submitted 29 December 2005
Posted 31 December 2005
  I recommend the Primary Papers

This study describes an interesting genetic link between PDE4B (phosphodiesterase 4B) and schizophrenia that may be related to a physical interaction with DISC1 (disrupted in schizophrenia 1), another gene associated with the psychiatric disorder. The study is highly suggestive of a role for the PDE4B/DISC1 complex in schizophrenia. However, the mechanistic model suggested by the authors whereby DISC1 sequesters PDE4B in an inactive state seems overly speculative, given the results presented in this paper and in prior studies that have examined the regulation of PDE4B by phosphorylation in the absence of DISC1.

View all comments by Angus Nairn

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Comment by:  Patricia Estani
Submitted 2 January 2006
Posted 2 January 2006
  I recommend the Primary Papers

Related News: Nature Makes a DISC1-Deficient, Forgetful Mouse

Comment by:  Anil Malhotra, SRF AdvisorKatherine E. Burdick
Submitted 7 March 2006
Posted 7 March 2006
  I recommend the Primary Papers

The two latest additions to the burgeoning DISC1 literature provide additional support for a role of this gene in cognitive function and schizophrenia, and suggest that more comprehensive studies will be useful as we move to a greater understanding of its role in CNS function. Koike et al. (2006) found that a relatively common mouse strain has a naturally occurring mutation in DISC1 resulting in a truncated form of the protein, similar in size (exon 7 vs. exon 8 disruptions) to that observed in the members of the Scottish pedigree in which the translocation was first detected. C57/BL/6J mice, into which mutant alleles were transferred, displayed significant impairments on a spatial working memory task similar to one used in humans (Lencz et al., 2003). These data are similar to those observed by our group (Burdick et al., 2005) and others (Callicott et al., 2005; Hennah et al., 2005; Cannon et al., 2005), although no study to date has utilized the same neurocognitive tasks. Lipska et al. (2006) report that genes and proteins (NUDEL, FEZ1) known to interact with DISC1 are also aberrant in schizophrenia postmortem tissue, with some evidence that DISC1 risk polymorphisms also influence expression across the pathway.

Taken together, these two papers suggest that the assessment of genes involved in the DISC1 pathway may be worthwhile in the evaluation of working memory function. To date, most studies have focused on risk alleles within DISC1, with little attention paid to the critical interacting genes. Studies are now underway assessing the relationship between FEZ1 and NUDEL and risk for schizophrenia in a number of populations, as well as studies examining their role in neurocognitive and neuroimaging parameters. Clearly, as the Lipska paper indicates, studies that attempt to assess multiple genes in this pathway will be critical, although the common concern of power in assessing gene-gene interactions, especially across multiple genes, may be a limitation. Moreover, these studies indicate that interaction studies will need to consider additional phenotypes other than diagnosis, and perhaps “purer” tasks of neurocognitive function may be worthwhile, as suggested by Koike et al. Finally, both of these papers underscore the fact that the next wave of genetic studies of schizophrenia will encompass the use of multiple probes, whether with neurocognitive assessments, postmortem analyses, or animal models of disease, amongst others, to fully validate the relationships between putative risk genes and the pathophysiology of schizophrenia and related disorders.


Burdick KE, Hodgkinson CA, Szeszko PR, Lencz T, Ekholm JM, Kane JM, Goldman D, Malhotra AK. DISC1 and neurocognitive function in schizophrenia. Neuroreport 2005; 16(12): 1399-1402. Abstract

Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8627-32. Epub 2005 Jun 6. Abstract

Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, Gasperoni T, Tuulio-Henriksson A, Pirkola T, Toga AW, Kaprio J, Mazziotta J, Peltonen L. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry, 2005; 62(11):1205-1213. Abstract

Hennah W, Tuulio-Henriksson A, Paunio T, Ekelund J, Varilo T, Partonen T, Cannon TD, Lonnquist J, Peltonen L. A haplotype within the DISC1 gene is associated with visual memory functions in families with high density of schizophrenia. Mol Psychiatry 2005; 10(12):1097-1103. Abstract

Lencz T, Bilder RM, Turkel E, Goldman RS, Robinson D, Kane JM, Lieberman JA. Impairments in perceptual competency and maintenance on a visual delayed match-to-sample test in first episode schizophrenia. Arch Gen Psychiatry 2003; 60(3):238-243. Abstract

View all comments by Anil Malhotra
View all comments by Katherine E. Burdick

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Comment by:  J David Jentsch
Submitted 7 March 2006
Posted 7 March 2006
  I recommend the Primary Papers

In their recent paper, Koike et al. provide new evidence in support of a genetic determinant of working memory function in the vicinity of the mouse DISC1 gene. They report their discovery of a naturally occurring DISC1 deletion variant in the 129S6/SvEv mouse strain that leads to reduced protein expression and that provides a potentially very important new tool for analyzing the cellular and behavioral phenotypes associated with DISC1 insufficiency. Given the strong evidence of a relationship between a cytogenetic abnormality that leads to DISC1 truncation in humans and major mental illness (Millar et al., 2000), this murine model stands to greatly serve our understanding of the molecular and cellular determinants of poor cognition in schizophrenia and bipolar disorder.

The authors are parsimonious in reminding us of the substantial limitations of models such as this. Specifically, the current approach does not allow for a clear statement that the DISC1 gene itself modulates the traits of interest. The DISC1 deletion variant may simply be in linkage disequilibrium with the actual phenotype-determining gene, and/or variation in DISC1 may influence cognition in a manner that is modified by a nearby genetic region. For example, Cannon et al. recently showed that a 4-SNP haplotype spanning DISC1 and an adjacent gene, translin-associated factor X (TRAX) is more predictive of anatomical and cognitive indices of reduced prefrontal cortical and hippocampal function than are any known haplotypes spanning DISC1 only. Clearly, additional consideration of the genetic environment in which DISC1 lies is necessary, and discovery of flanking regions that contain modifiers of the actions of DISC1, and vice versa, would be extremely interesting.

The greatest impact of the paper by Koike et al. is hinged on the fact that mice carrying one or two copies of the deletion variant exhibit poor choice accuracy in a delayed non-match to position task. Specifically, mutant DISC1 mice made fewer correct choices than did wild-type littermate C57 mice. Because a procedure such as this is necessarily psychologically complex, performance failure is hardly prima facie evidence for impairments of spatial working memory, or for prefrontal cortical dysfunction, in general. Nevertheless, the data are remarkable in establishing a phenotypic bridge between species and in laying the foundation for more sophisticated behavioral studies that will narrow in on the psychological constructs and neural systems affected by variation in this genetic region. Through facilitating a greater understanding of the cognitive phenotypes associated with DISC1 variation, the model should open doors to understanding key phenotypic aspects of schizophrenia and bipolar disorder.


Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci U S A. 2006 Feb 16; [Epub ahead of print] Abstract

Millar JK, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, Devon RS, Clair DM, Muir WJ, Blackwood DH, Porteous DJ. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet. 2000 May 22;9(9):1415-23. Abstract

Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, Gasperoni T, Tuulio-Henriksson A, Pirkola T, Toga AW, Kaprio J, Mazziotta J, Peltonen L. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry. 2005 Nov;62(11):1205-13. Abstract

View all comments by J David Jentsch

Related News: Nature Makes a DISC1-Deficient, Forgetful Mouse

Comment by:  Kirsty Millar
Submitted 13 March 2006
Posted 13 March 2006
  I recommend the Primary Papers

Disrupted In Schizophrenia 1 was first identified as a genetic susceptibility factor in schizophrenia because it is disrupted by a translocation between chromosomes 1 and 11 in a large Scottish family with a high loading of schizophrenia and related mental illness. Since then, numerous genetic studies have implicated DISC1 as a risk factor in psychiatric illness in several populations. Given the limitations on studies using brain tissue from patients, an obvious next step was to engineer knockout mice, but these have been slow in coming. As a first step toward this, Kioke and colleagues now report an unexpected naturally occurring genetic variant in the 129/SvEv mouse strain.

Kioke et al. report that the 129/SvEv mouse strain carries a 25 bp deletion in DISC1 exon 6, and that this results in a shift of open reading frame and introduction of a premature stop codon. Several embryonal stem cell lines have been isolated for the 129 strain, favoring it for gene targeting studies. However, this strain has a number of well-established behavioral characteristics ( Therefore, to assign any phenotype specifically to the DISC1 deletion variant, the 129 DISC1 variant had to be transferred to a C57BL/6J background, with its own, rather different but equally characteristic behavior ( There were no detectable gross morphological alterations in the prefrontal cortex, cortex, and hippocampus on transferring the 129 DISC1 locus onto the C57BL/6J background. However, the mutation did result in working memory deficits, consistent with several reports linking DISC1 to cognition.

It is difficult to know what phenotype to expect from a mouse model for schizophrenia, but in humans it is widely believed that mutations confer only a susceptibility to developing illness. Many susceptible individuals function apparently normally, although subtle neurological endophenotypes are detectable. In individuals who do go on to develop schizophrenia, cognitive deficits are a major characteristic. These mild cognitive deficits in mice with loss of DISC1 function are therefore close to what we might predict.

The molecular mechanism by which DISC1 confers susceptibility to psychiatric illness is the subject of some debate. Sawa and colleagues have suggested that a mutant truncated protein resulting from the t(1;11) is responsible for the psychiatric disorders in the Scottish family. Millar and colleagues, however, report that there is no evidence for such a hypothetical protein in t(1;11) cell lines, but rather that the levels of DISC1 transcript and protein are reduced, consistent with a haploinsufficiency model. Identification of the deletion in mice may shed further light on this debate, since while the mutation does not affect DISC1 transcript levels, no mutant truncated protein is detectable, even though such a protein might theoretically be produced as a result of the premature stop codon. Moreover, both homozygotes and heterozygotes have cognitive impairment, demonstrating that DISC1 haploinsufficiency is sufficient to affect central nervous system function.

In this initial study, Kioke and colleagues have left many questions unanswered. In particular, the behavioral studies are limited to one working memory task and one test of locomotion. Ideally, a whole battery of behavioral and cognitive tests should be performed. Since 129/SvEv mice reportedly have impaired hippocampal function, high levels of anxiety-like behavior and altered NMDA receptor-related activity, it will be interesting to discover which, if any, of these phenotypes also co-segregate with the 129 DISC1 variant. It is also interesting to note that the 129 strain is effectively a null for full-length DISC1, but with no gross alteration in brain morphology. This has to be reconciled with the observed effect of transient RNAi mediated down-regulated expression in utero (Kamiya et al., 2005) and the possible, but still anecdotal observation of embryonic lethality in experimental DISC1 knockouts.

View all comments by Kirsty Millar

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Comment by:  Bita Moghaddam, SRF Advisor
Submitted 3 April 2006
Posted 3 April 2006

Cortical dysfunction in schizophrenia has been attributed to both inhibitory GABA and excitatory glutamate neurotransmission. Abnormalities in cortical GABA neurons have been observed primarily in the subset of GABA interneurons that contain the calcium-binding protein parvalbumin (PV). The glutamatergic dysfunction is suspected primarily because reducing glutamate neurotransmission at the NMDA receptors produces behavioral deficits that resemble symptoms of schizophrenia. These two mechanisms have been generally treated as separate conjectures when conceptualizing theories of schizophrenia. The paper by Cunningham et al. demonstrates that, in fact, disruptions in PV positive cortical GABA neurons and blockade of NMDA receptors produce similar disruptions to the function of cortical networks.

The authors used lysophosphatidic acid 1 receptor (LPA-1)-deficient mice which, they argue, are a relevant model of schizophrenia because these animals display sensorimotor gating deficits, a critical feature of schizophrenia. They demonstrate that, similar to schizophrenia, the number of PV positive GABA neurons is significantly reduced in LPA-1-deficient mice. Furthermore, the γ frequency network oscillation disruptions they observe in these animals are similar to those seen in wild-type mice treated with the NMDA antagonist ketamine. (γ oscillations have been associated with sensory processing and deficits in γ rhythm generation have been reported in patients with schizophrenia during performance of sensory processing tasks.) The disruptive effect of ketamine on γ oscillations was mediated by a decrease in the output of fast-spiking GABA interneurons causing a disinhibition (i.e., increased firing) of glutamate neurons. These findings are significant because they suggest that cortical NMDA hypofunction may cause the reported GABA interneuron deficits in schizophrenia.

View all comments by Bita Moghaddam

Related News: Gamma Band Plays a Sour Note in Entorhinal Cortex of Schizophrenia Models

Comment by:  Patricio O'Donnell, SRF Advisor
Submitted 7 April 2006
Posted 7 April 2006

Animal models of schizophrenia and other psychiatric disorders are receiving increasing interest, as they provide useful tools to test possible pathophysiological scenarios. Some models have been tested with a wide array of approaches and many others continue to develop. If one focuses on possible cortical alterations, a critical issue emerging from many different lines of research using several different models is the apparent contradiction between the hypo-NMDA concept and the data suggesting a loss of cortical interneurons. Is there a hypo- or a hyperactive cortex?

This conundrum has been present since earlier days in the postmortem and clinical research literature, but with the advent of more refined animal models, it may be time to provide a possible way in which these discrepant sets of data can be reconciled. Whether this was the authors’ intention or not, the article by Cunningham and colleagues is an excellent step in that direction. This study used mice deficient in lysophosphatidic acid 1 receptor, a manipulation that reduced the GABA and parvalbumin-containing interneuron population by about 40 percent and disrupted γ (rapid) oscillations in the entorhinal cortex. A key element in this study was the finding that a similar alteration in rapid cortical oscillations was observed with the noncompeting NMDA antagonist ketamine. There is a large body of evidence indicating that interneurons (in particular, the fast-spiking type that include parvalbumin-positive neurons) are critical for synchronization of fast cortical oscillatory activity. As fast oscillations can be envisioned as phenomena with deep impact on cognitive functions, these findings may have bearing on possible pathophysiological scenarios underlying cognitive deficits in schizophrenia. This article does provide a strong indication that antagonism of NMDA receptors may selectively target cortical interneurons. This is in agreement with the work of Bita Moghaddam, who has shown that noncompeting NMDA antagonists can indeed increase pyramidal cell firing and glutamate levels in the prefrontal cortex. Thus, it is conceivable that psychotomimetic agents such as PCP or ketamine exert their cognitive effects by impairing interneuronal activity, hampering the fine-tuning of pyramidal cell firing that is expressed as fast cortical oscillations.

View all comments by Patricio O'Donnell

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Comment by:  Ali Mohammad Foroughmand
Submitted 16 December 2006
Posted 16 December 2006
  I recommend the Primary Papers

Related 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 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 Sawa

Related 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 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 Ross

Related 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 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

Related News: Inducing Schizophrenic Behavior? Researchers Roll Out New DISC1 Mouse

Comment by:  John RoderSteven Clapcote
Submitted 17 September 2007
Posted 17 September 2007

This is a useful model from Pletnikov, Ross, and colleagues, but like all models, it has some limitations. Since DISC1 is known to have a strong role in development and physiology, the development of inducible mutants is necessary to separate the two.

In the TeT-off system used in the paper, mice must be treated with doxycycline for their entire lives to keep the expression of this gene off. Doxycycline must be used at high levels and may have side effects when used this long. The TeT-on system is better because doxycycline is only used transiently for 1 week for maximum induction then washed away. The TeT-on system is also available for the same promoter used in the paper, that of the CaMKII gene.

The phenotype of reduced neurite length was obtained from in vitro neuron cultures, which are prone to artifacts. There are ways of labeling these neurons in vivo for measuring neurite length and spines. The brain phenotype was obtained by MRI. There are ways, such as adding manganese, of enhancing active pathways. This has been done in the bird brain to map song pathways.

The behavioral phenotype was similar to the recent paper from the Sawa group (Hikida et al., 2007) in that it also analyzed a transgenic mouse expressing the same C-terminal truncation of the human DISC1 gene, using the same CaMKII promoter. An important difference in the findings was a reduction of murine DISC1 (50 percent at protein level) in the Pletnikov et al. mice but none in the Sawa group mice. This issue is important because of a recent paper in Cell by the Song group (Duan et al., 2007). In that paper, RNAi was used to reduce wild-type native murine DISC1. Individual neurons with targeted DISC1 knockdown showed accelerated neurite development, greater synapse formation and enhanced excitability. Hippocampal granule cells showed accelerated morphological integration resulting in mispositioning. Unfortunately, in the Song paper they analyzed only cells with complete or no knockdown of DISC1. Partial knockdown vectors were made that achieved 75 percent reduction at the protein level but were not analyzed. Only then would it be possible to compare these morphological data with those from Pletnikov et al., which was a 50 percent reduction. Another difference was that the Song group found that DISC1 needed to interact with Nudel. Pletnikov et al. found normal levels of Nudel in the mice but lower LIS1, which could explain the brain development phenotype.

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Related News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

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, so it is puzzling they see expression in the cerebellum. Expressed DISC1 bound to endogenous mouse Nudel and LIS1, presumably exerting a dominant-negative effect. Induction of the C-terminus DISC1 at day 7, but not in the adult, led to deficits in working memory, the forced swim test, and sociability. It would have been reassuring if these tasks were validated using antipsychotics and antidepressants. It is not clear in this study why the female C57 was used as a standard opponent mouse, and what genders of DISC1 mice have been used. Even though young C57 females (6 weeks old) were used as neutral partners, the data might be interpreted also as impaired sexual motivation in DISC1-Tg-Tm7 mice.

The authors made an attempt to translate their mouse data (low sociability) into a human population and found an association between DISC1 haplotypes and social impairments in a Finnish population (n = 232 samples), which supports a DISC1 role in social behavior, one of schizophrenia's symptoms. It would be useful to distinguish deficits in social interactions and impaired sexual behavior.

Deficits in working memory are also an important schizophrenia endophenotype, and it would be interesting to measure how specific the cognitive deficit is in DISC1-Tg-Tm-7 mice, estimating associative memory in classical fear conditioning, for example.

Induction of the transgene early in development to day 7 resulted in small changes in dendritic complexity in granule cells in the dentate gyrus. It is surprising larger changes were not observed. The role of DISC1 in the adult self-renewing progenitor cells in the dentate switches, so that DISC1 acts as a brake for dendritic complexity and migration (Duan et al., 2007). Thus, reductions in DISC1 in the adult dentate gyrus granule cells lead to enhanced dendrite growth/complexity.

In the adult, DISC1 was shown to interact with Nudel in controlling adult neurogenesis and development. It is of interest that in the Li et al. paper the transgene also perturbs native DISC1 binding to Nudel at day 7 but not adult. Synaptic transmission was reduced in CA1. It would have been nice to see a recording from dentate granule cells in which changes in dendritic complexity were found.


Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U, Kudo C, Okawa M, Ross CA, Hatten ME, Nakajima K, Sawa A. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol. 2005 Dec 1;7(12):1167-78. Abstract

Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007 Sep 21;130(6):1146-58. Abstract

View all comments by John Roder

Related News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

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 disadvantages: 1) mice with a spontaneous mutation in an exon, which seem to lack some, but not all, DISC1 isoforms, from Gogos’s lab (see Koike et al., 2006; Ishizuka et al., 2007); 2) mice with mutations induced by a mutagen from Roder’s lab (Clapcote et al., 2007); 3) transgenic mice that express a dominant-negative mutant DISC1 from Sawa’s lab (Hikida et al., 2007); 4) transgenic mice that express a dominant-negative mutant DISC1 in an inducible manner from Pletkinov’s lab (Pletnikov et al., 2007); and 5) the mice from Silva’s and Cannon’s labs.

It is impossible to reach a firm conclusion on how the Scottish mutation of the DISC1 gene leads to molecular dysfunction until the data from autopsied brains of patients in the Scottish family become available. Millar and colleagues have published data of DISC1 in lymphoblastoid cells from the family members and propose an intriguing suggestion of how DISC1 is potentially disturbed in the pedigree (Millar et al., 2005); however, this remains in the realm of hypothesis/suggestion from peripheral cells. Thus, it is very important to compare the various types of DISC1 animal models in approaching how disturbance of DISC1 in brain leads to the pathophysiology of schizophrenia and related disorders.


Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3693-7. Abstract

Ishizuka K, Chen J, Taya S, Li W, Millar JK, Xu Y, Clapcote SJ, Hookway C, Morita M, Kamiya A, Tomoda T, Lipska BK, Roder JC, Pletnikov M, Porteous D, Silva AJ, Cannon TD, Kaibuchi K, Brandon NJ, Weinberger DR, Sawa A. Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Mol Psychiatry. 2007 Oct ;12(10):897-9. Abstract

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;54(3):387-402. Abstract

Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue R, Andradé 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. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14501-6. Abstract

Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, Mori S, Moran TH, Ross CA. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2007 Sep 11; Abstract

Millar JK, Pickard BS, Mackie S, James R, Christie S, Buchanan SR, Malloy MP, Chubb JE, Huston E, Baillie GS, Thomson PA, Hill EV, Brandon NJ, Rain JC, Camargo LM, Whiting PJ, Houslay MD, Blackwood DH, Muir WJ, Porteous DJ. DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science. 2005 Nov 18;310(5751):1187-91. Abstract

View all comments by Akira Sawa

Related News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

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 to misregulate cAMP signaling (Millar et al., 2005; Murdoch et al., 2007).

Then, back-to-back came two variants of DISC1 transgenic models from Johns Hopkins University (Pletnikov et al., 2007; Hikida et al., 2007) (see also SCZ Forum). Both Pletnikov and Hikida overexpressed a truncated form of DISC1 under the control of the CaMKII promoter (in Pletnikov’s case with an inducible CaMKU promoter). Both groups reported brain structural and behavioral abnormalities that aligned rather nicely with the earlier work of Clapcote et al. (2007). Pletnikov et al. showed that neurite outgrowth was attenuated in primary cortical neurons. They also showed that endogenous DISC1, LIS1, and SNAP25, but not NDEL1 or PSD-95, was reduced in mouse forebrain.

Now, Li et al. (2007) introduce yet another transgenic DISC1 model mouse, this time overexpressing a carboxy tail fragment of DISC1, so the opposite end of the DISC1 molecule from that overexpressed by Pletnikov and by Hikida. Intriguingly, Li et al. (as with all the preceding models) report significant behavioral differences for wild-type littermates. The point of added interest and significance here is that by using an inducible transgenic construct, they could elicit behavioral abnormalities if carboxy terminal DISC1 was expressed on postnatal day 7 only, but not in adult life. What are we to make of this and how do the models align? Li et al. interpret their results to suggest that DISC1 plays a crucial role, through NDEL1 and LIS1, in postnatal (but not adult) brain development. This study obviously raises some key questions. What is the developmental window of DISC1 effect? How can the lack of effect in the adult be reconciled with the rather striking effect on neurogenesis consequent upon downregulation of DISC1 in the adult mouse brain reported by Duan et al. (2007). And if overexpressing 5’ (Hikida, Pletnikov) or 3’ constructs (Li) can elicit similar phenotypes as seen in ENU-induced missense variants within exon 2 (Clapcote), can we come up with a unifying explanation? Perhaps not yet, but these various mouse models certainly emphasize the value of a multi-pronged mouse modeling approach. Combinations of “null,” transgenic, inducible, and missense mutants will help dissect the underlying processes. These studies also suggest that a variety of DISC1 variants in humans might elicit rather similar and also subtly different phenotypes. Indeed, Li et al. try to link their findings on the mouse to human studies, but here I feel there is cause for caution. The genetic association referred to maps to a haplotype in a quite distinct region of DISC1 and the direct or indirect functional effect of the haplotype is far from clear. It is, however, conceptually unlikely that this risk haplotype has a specific or restricted effect on Nudel and/or Lis1 binding. The corollary between a genetic association for a selected, but poorly defined sub-phenotype of schizophrenia with a poorly defined behavioral phenotype in the mouse may be a corollary too far too soon. Finally, whereas the focus of attention by Li, Pletnikov, and Hikida has been on the well-established/neurodevelopmental role of NDEL1 (and LIS1), the potential role of PDE4B both in neurosignaling (related to behavior, learning, and memory) and possibly also neurodevelopment should not be overlooked. In this regard it is noteworthy that PDE4 interacts both with the head and the carboxy tail domain of DISC1 (Hannah et al., 2007) and this most likely contributes to the phenotype in all the models described to date.


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;54(3):387-402. Abstract

Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue R, Andradé 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. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14501-6. Abstract

Ishizuka K, Chen J, Taya S, Li W, Millar JK, Xu Y, Clapcote SJ, Hookway C, Morita M, Kamiya A, Tomoda T, Lipska BK, Roder JC, Pletnikov M, Porteous D, Silva AJ, Cannon TD, Kaibuchi K, Brandon NJ, Weinberger DR, Sawa A. Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Mol Psychiatry. 2007 Oct 1;12(10):897-9. Abstract

Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3693-7. Abstract

Li W, Zhou Y, Jentsch JD, Brown RA, Tian X, Ehninger D, Hennah W, Peltonen L, Lönnqvist 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. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18280-5. Abstract

Millar JK, James R, Christie S, Porteous DJ. Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria. Mol Cell Neurosci. 2005 Dec 1;30(4):477-84. Abstract

Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007 Sep 21;130(6):1146-58. Abstract

Murdoch H, Mackie S, Collins DM, Hill EV, Bolger GB, Klussmann E, Porteous DJ, Millar JK, Houslay MD. Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. J Neurosci. 2007 Aug 29;27(35):9513-24. Abstract

Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, Mori S, Moran TH, Ross CA. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2007 Sep 11; [Epub ahead of print] Abstract

View all comments by David J. Porteous

Related News: DISC1 Is Critical for Axon Terminals in Adult Hippocampus

Comment by:  Jill MorrisKate Meyer
Submitted 3 October 2008
Posted 6 October 2008
  I recommend the Primary Papers

The elegant research by Faulkner and colleagues, along with their previous work (Duan et al., 2007), clearly demonstrates a role for DISC1 in regulating the timing of neuronal development in the adult brain. The loss of Disc1 in adult-born dentate granule cells resulted in aberrant axonal targeting and accelerated mossy fiber maturation. Although it is hypothesized that the hippocampus is involved in the pathophysiology of schizophrenia, the cellular and molecular underpinnings of hippocampal dysfunction are unknown. However, it is becoming apparent that Disc1 is a regulator of granule cell integration and maturation in the adult hippocampus. The function of adult-born granule cells and the contribution they make to hippocampal function is, of course, yet to be fully elucidated. In the context of schizophrenia, though, it may be that abnormal incorporation of newborn granule cells into the hippocampal network—perhaps caused by mutations in key genes such as Disc1—is a post-developmental trigger which leads to the onset of disease symptoms.

The finding that Disc1 regulates mossy fiber targeting and synapse formation is also intriguing on a more general level. There is much research suggesting that schizophrenia is a disease of the synapse, likely involving several neurotransmitter systems. A role for Disc1 in axon outgrowth and synapse formation would certainly be a means through which Disc1 disruption could affect the hippocampal trisynaptic circuit. Next, we as researchers will have to determine the molecular mechanisms by which Disc1 is regulating neuronal development and axonal targeting. Based on the work in the developing and adult brain, Disc1 has multiple cellular roles involving a long list of interactors. The challenge is determining which Disc1 functions and pathways are relevant to the schizophrenia phenotype.


Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007 Sep 21;130(6):1146-58. Abstract

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Related News: DISC1 Players Gird For Adult Neurodevelopment

Comment by:  Kevin J. Mitchell
Submitted 8 October 2009
Posted 8 October 2009

The seminal identification of mutations in DISC1 associated with schizophrenia and other psychiatric disorders raises several obvious questions: what does the DISC1 protein normally do? What are its biochemical and cellular functions, and what processes are affected by its mutation? How do defects in these cellular processes ultimately lead to altered brain function and psychopathology? Which brain systems are affected and how? Similar questions could be asked for the growing number of other genes that have been implicated by the identification of putatively causal mutations, including NRG1, ERBB4, NRXN1, CNTNAP2, and many copy number variants. Finding the points of biochemical or phenotypic convergence for these proteins or mutations may be key to understanding how mutations in so many different genes can lead to a similar clinical phenotype and to suggesting points of common therapeutic intervention.

The papers by Kim et al. and Enomoto et al. add more detail to the complex picture of the biochemical interactions of DISC1 and its diverse cellular functions. The links with Akt and PTEN signaling are especially interesting, given the previous implication of these proteins in schizophrenia and autism. Akt, in particular, may provide a link between Nrg1/ErbB4 signaling and DISC1 intracellular functions.

These studies also reinforce the importance of DISC1 and its interacting partners in neurodevelopment, specifically in cell migration and axonal extension. In particular, they highlight the roles of these proteins in postnatal hippocampal development and adult hippocampal neurogenesis. They also raise the question of which extracellular signals and receptors regulate these processes through these signalling pathways. The Nrg1/ErbB4 pathway has already been implicated, but there are a multitude of other cell migration and axon guidance cues known to regulate hippocampal development, some of which, for example, semaphorins, signal through the PTEN pathway.

Whether or how disruptions in these developmental processes contribute to psychopathology also remains unclear. It seems likely that the effects of mutations in any of these genes will be highly pleiotropic and have effects in many brain systems. The reported pathology in schizophrenia is not restricted to hippocampus but extends to cortex, thalamus, cerebellum, and many other regions. Similarly, while the cognitive deficits receive a justifiably large amount of attention, given that they may have the most clinical impact, motor and sensory deficits are also a stable and consistent part of the syndrome that must be explained. Pleiotropic effects on prenatal and postnatal development, as well as on adult processes, may actually be the one common thread characterizing the genes so far implicated. These new papers represent the first steps in the kinds of detailed biological studies that will be required to make explanatory links from mutations, through biochemical and cellular functions, to effects on neuronal networks and ultimately psychopathology.

View all comments by Kevin J. Mitchell

Related News: DISC1 Players Gird For Adult Neurodevelopment

Comment by:  Peter PenzesMichael Cahill
Submitted 8 October 2009
Posted 8 October 2009

DISC1 disruption by chromosomal translocation cosegregates with several neuropsychiatric disorders, including schizophrenia (Blackwood et al., 2001; Millar et al., 2000). Recent attention has focused on the effects of DISC1 on the structure and function of the dentate gyrus, one of the few brain regions that exhibit neurogenesis throughout life. The downregulation of DISC1 has several deleterious effects on the dentate gyrus, including aberrant neuronal migration (Duan et al., 2007). However, the mechanisms through which DISC1 regulates the structure and function of the dentate gyrus remain unknown. The dentate gyrus and its output to the CA3 area, the mossy fiber, show several abnormalities in schizophrenia and other neuropsychiatric diseases (Kobayashi, 2009). Thus, understanding how a gene associated with neuropsychiatric disease, DISC1, mechanistically impacts the dentate gyrus is an important question with much clinical relevance.

The recent papers by Kim et al. and Enomoto et al. characterize an interaction between DISC1 and girdin (also known as KIAA1212), and reveal how girdin, and the interaction between DISC1 and girdin, impact axon development, dendritic development, and the proper positioning of newborn neurons in the dentate gyrus. Girdin normally stimulates the function of AKT (Anai et al., 2005), and Kim et al. show that DISC1 binds to girdin and inhibits its function. Thus, the loss of DISC1 leaves girdin unopposed, resulting in excessive AKT signaling. Indeed, the developmental defects in neurons lacking DISC1 can be rescued by pharmacologically blocking the activation of an AKT downstream target. However, as shown by Enomoto et al., the loss of girdin produces deleterious effects on neuronal morphology, suggesting that a proper balance of girdin function is crucial.

Collectively, these studies thoroughly characterize the interaction between DISC1 and girdin, and shed much light on the consequences of this interaction on neuronal morphology as well as on the positioning of neurons in the dentate gyrus. The role of girdin in the pathology of neuropsychiatric diseases is unknown, and remains an interesting question for the future. Characterizing the molecules that act up- or downstream of DISC1 remains an important area of investigation and could aid the development of pharmacological interventions in the future. It’s intriguing that DISC1 acting through girdin regulates the activity of AKT as AKT1 was previously identified as a schizophrenia risk gene (Emamian et al., 2004). This suggests a convergence of multiple schizophrenia-associated genes in a shared pathway, and thus it will be important to determine if the DISC1-girdin-AKT1 pathway is particularly vulnerable in neuropsychiatric disorders.


Blackwood DH, Fordyce A, Walker MT, St Clair DM, Porteous DJ, Muir WJ. Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet . 2001 Aug 1 ; 69(2):428-33. Abstract

Millar JK, Christie S, Semple CA, Porteous DJ. Chromosomal location and genomic structure of the human translin-associated factor X gene (TRAX; TSNAX) revealed by intergenic splicing to DISC1, a gene disrupted by a translocation segregating with schizophrenia. Genomics . 2000 Jul 1 ; 67(1):69-77. Abstract

Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y, Liu XB, Yang CH, Jordan JD, Ma DK, Liu CY, Ganesan S, Cheng HJ, Ming GL, Lu B, Song H. Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell . 2007 Sep 21 ; 130(6):1146-58. Abstract

Kobayashi K. Targeting the hippocampal mossy fiber synapse for the treatment of psychiatric disorders. Mol Neurobiol . 2009 Feb 1 ; 39(1):24-36. Abstract

Anai M, Shojima N, Katagiri H, Ogihara T, Sakoda H, Onishi Y, Ono H, Fujishiro M, Fukushima Y, Horike N, Viana A, Kikuchi M, Noguchi N, Takahashi S, Takata K, Oka Y, Uchijima Y, Kurihara H, Asano T. A novel protein kinase B (PKB)/AKT-binding protein enhances PKB kinase activity and regulates DNA synthesis. J Biol Chem . 2005 May 6 ; 280(18):18525-35. Abstract

Emamian ES, Hall D, Birnbaum MJ, Karayiorgou M, Gogos JA. Convergent evidence for impaired AKT1-GSK3beta signaling in schizophrenia. Nat Genet . 2004 Feb 1 ; 36(2):131-7. Abstract

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