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Human-like DISC1 Mutation Causes Morphological and Cognitive Deficits

21 May 2008. Mutations in disrupted in schizophrenia (DISC1), a putative schizophrenia gene, interfere with the production and maturation of new neurons in the adult mouse brain and may interrupt brain circuits in the hippocampus and the prefrontal cortex, two regions associated with schizophrenia, according to a new study in the May 13 PNAS. The findings, reported by Joseph Gogos, Maria Karayiorgou, and colleagues at Columbia University, New York, may help explain why people with a chromosomal rearrangement in the middle of the DISC1 gene are at high risk for major mental illnesses such as schizophrenia and bipolar disorder.

The original, and best, evidence that DISC1 is involved in schizophrenia comes from an extended Scottish family whose members carry the chromosomal rearrangement leading to a disruption of the DISC1 gene. The disruption is a translocation of a piece of DNA from the middle of the DISC1 gene, resulting in a loss of several major DISC1 isoforms, and the possible production of a truncated protein.

The Columbia researchers set out to recapitulate that same mutation in a mouse model by adding a stop codon in exon 8 and a polyadenylation signal downstream to make the mouse gene behave more like the mutated human gene. According to Gogos, during the course of this work they unexpectedly discovered a natural deletion in the middle of the mouse Disc1 gene that spontaneously arose in the 129S6 strain. The researchers reported two years ago that the spontaneous mutation, a deletion of 25 bases, introduces a stop codon in exon 7 that truncates the mouse 129S6 Disc1 protein (see SRF related news story). As a result, the genetically engineered mouse strain contains two termination codons and a polyadenylation site near the translocation breakpoint of the human gene.

Kvajo and colleagues report that their protein expression analysis, using antibodies against the N-terminal and C-terminal domains of Disc1, confirmed that key and well-characterized long isoforms of Disc1 are eliminated by the introduced mutations. The authors argue that this is in contrast to a recent study by a collective of other DISC1 research groups (Ishizuka et al., 2007), which reported that long Disc1 isoforms are expressed in these mice. In e-mail interviews with SRF, Gogos and colleagues suggested that the antibodies to Disc1 used by other research groups may not be ideal to probe complex brain extracts.

Overall, the researchers say, the genetic lesion introduced into the mouse Disc1 gene closely models the Scottish mutation by virtue of where the truncating lesion is and because it only affects a subset of Disc1 isoforms. (Long Disc1 isoforms are eliminated, while short N-terminal isoforms of the gene, unaffected by the translocation, are preserved, they say).

In the current paper, joint first authors Mirna Kvajo, Heather McKellar, and Alexander Arguello have characterized aspects of the anatomical and behavioral phenotype emerging as a result of this genetic lesion. Their data suggest that Disc1 may be important for proper maturation of new neurons in the adult brain and for maintenance of neuronal circuitry that is involved in working memory.

Effects on form
The authors examined mouse brain for signs of morphological changes in the Disc1 mutants. They found no gross morphological changes in either the prefrontal cortex (PFC) or the hippocampus, though they did find a statistically significant decrease (14 percent) in PFC volume compared to control mice. At a higher level of resolution, the researchers found significant differences in the immature and mature neurons in the dentate gyrus, a site of adult neurogenesis. There, immature (i.e., doublecortin-positive) neurons seemed to migrate farther than normal, with a greater fraction reaching the outer granule cell layer. The apical dendrites in these neurons were also abnormal. Apical dendrites usually lie perpendicular to the surface of the subgranular zone of the dentate gyrus, where new neurons form. But dendrites in about 30 percent of immature neurons in mutant Disc1 mice were statistically outside the normal orientation. It is not clear if this reorientation of the dendrites is related to their ability to migrate farther, but that is a possibility given that the maturation of newly born neurons is tightly coupled to their migration. The researchers also found that the numbers of immature neurons were lower in Disc1 mutants (by ~20 percent), and that neurogenesis was down by about the same degree (as judged by mitotic incorporation of bromodeoxyuridine).

Morphological changes are not restricted to immature neurons. Kvajo, McKellar, and colleagues found that mature neurons are also compromised in the mutant mouse dentate gyrus (DG). Again, dendrite orientation was off by up to 40 percent, and twice as many mature neurons had dendrite angles outside the normal range. Dendrite lengths were also decreased by about 25 percent in mutant animals, though this was much more pronounced in the outer layers of the granule cell layer of the DG. This again, suggests that Disc1-compromised neurons may have problems maturing. “The lack of an effect in the bottom layer is consistent with our observation of near-normal dendritic growth in newly born neurons and suggests that impaired Disc1 function specifically leads to a halting of dendritic growth during the postnatal maturation of granule cells in the DG,” write the authors.

Effects on function
Behaviorally, the Disc1 mutant mice show deficits in working memory that suggest a problem in the prefrontal cortex. When the authors tested the mice in several hippocampal-dependent paradigms, including the Morris water maze, novel object recognition, and contextual fear conditioning, they found no difference from controls. However, when they used a two-choice, delayed nonmatch (DNMP) to position task, the mutant mice, both heterozygotes and homozygotes, performed statistically worse. Arguello explained that, although the DNMP task demands that the animals retain information over shorter periods of time, there are several trials a day and the two samples within a trial require them to update working memory. As with other spatial working memory tasks in rodents, this test depends on interactions between the PFC and hippocampus, but the exact role played by each is controversial. “This task creates a potential conflict because animals may be confused about the choices they are facing due to irrelevant information from within the trial or the previous trial,” explained Arguello in an interview with SRF. “Resolving this type of interference is something the PFC does and is part of the executive control of the PFC,” he said. Problems in the PFC are believed to be at least partly responsible for deficits in a whole range of working memory tasks in schizophrenia patients.

What does this model tell us about the role of DISC1? “If we look in the adult CA1 we don’t see a morphological deficit, we see an electrophysiological deficit, so maybe this selectivity says something about the necessity for Disc1 to be present in adulthood in the dentate gyrus, where, incidentally, Disc1 expression is strongest,” Kvajo told SRF. The authors found that under baseline conditions synaptic transmission in the CA1 of the hippocampus was normal, as was paired-pulse facilitation and long-term potentiation, both measures of neuronal plasticity. But the authors did find that short-term potentiation was significantly reduced in mutant mice.

So if Disc1 seems so crucial for the dentate gyrus and the hippocampus, then why are the mice deficient in tasks that depend on the PFC? Arguello offered a few possibilities, though he cautioned that they are highly speculative. The first is that the dentate gyrus plays a role in memory that has not been fully appreciated. “There is some recent evidence indicating that in the dentate gyrus, functionally knocking out NMDA receptors can affect working memory performance,” he said. Another possibility is that the primary deficit is in the hippocampus and that across the course of development the abnormal structural changes in the hippocampus can functionally affect the PFC. “So the idea is that a primary structural abnormality in the hippocampus can cause a secondary functional abnormality in PFC,” he said. Arguello said that they are planning to test these theories using various behavioral tasks that differentially engage cognitive networks of the brain and by looking for physiological changes.

Whether these findings in mice will have any bearing on the human condition remains to be determined. “While there is some evidence that adult neurogenesis may be implicated in mental disorders, it is hard to say exactly how these changes relate to the human condition because, in this respect, we know too little about the situation in humans. However, the really important thing about our model, and what makes it stand out, is that we have a model that is as close to the human mutation as can be. We have used a disease-oriented approach, which is important if you want to figure out what DISC1 does in schizophrenia specifically, or in mental disorders,” said Kvajo.—Tom Fagan.

Kvajo M, McKellar H, Arguello PA, Drew LJ, Moore H, MacDermott AB, Karayiorgou M, Gogos JA. A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. Proc Natl Acad Sci U S A. 2008 May 13;105(19):7076-81. Epub 2008 May 5. Abstract

Comments on News and Primary Papers
Comment by:  David J. Porteous, SRF Advisor
Submitted 16 May 2008
Posted 16 May 2008

This paper is an update on the original report from the Gogos group (Koike et al., 2006) on the phenotype of mice carrying a genetically modified version of the 129 strain derived Disc1 gene and joins an already impressive list of Disc1 mouse models with associated SZ related phenotypes. Koike et al. (2006) attempted to knock out the Disc1 locus by homologous recombination in 129 derived mouse embryonal stem cells. The objective was to mimic as best as possible the effect of the t(1;11) balanced translocation that segregated with SZ and related major mental illness in a large Scottish family (Blackwood et al., 2001) and which led to the identification at the breakpoint of the DISC1 gene (Millar et al., 2000). In the event, this didn’t quite happen as planned, but a fortuitous and positive outcome was the generation of a transgene insertion which introduced two termination codons in exons 7 and 8. Simultaneously, it was recognized that the Disc1 locus in the 129 strain actually already carries a 25 bp deletion, so is naturally a “knockout” of sorts.

The 129 mouse strain is well known to have a number of behavioral differences relative to the C57Bl6 strain. Backcrossing the transgene modified 129 Disc1 allele onto a C57Bl6 background allowed the Gogos group to isolate the Disc1 locus effect from the overall 129 strain effects. They reported that mice either heterozygous or homozygous for the transgene modified 129 Disc1 allele showed a deficit in a choice delay measure of working memory compared to C57Bl6 mice. A flurry of further Disc1 mouse models followed, with a ubiquitous and a conditional transgene model overexpressing a 5’ truncate DISC1 transgene from the Sawa and Ross groups at Johns Hopkins (Hikida et al., 2007; Pletnikov et al., 2008), an inducible C-terminal truncate DISC1 transgenic overexpression model from the Cannon group (Li et al., 2007), and two different ENU-induced Disc1 missense mutants from the Roder group (Clapcote et al., 2007). A rather consistent picture emerges from these studies of brain morphological and working memory deficits consistent with the neurodevelopmental hypothesis in SZ. Uniquely to date, the ENU missense mutation study of Clapcote et al. (2007) demonstrated behavioral effects that could be partially or wholly rescued by antipsychotic or antidepressant treatment. Furthermore, the missense mutations affected binding sites for the DISC1 interactor PDE4B, offering a molecular mechanism to explain the behavioral and drug effects.

So what does the latest study from Kvajo et al. (2008) add to the existing picture? Before examining this, it is appropriate to make one or two qualifying comments about this specific model. The reported effects apply only to the transgenically modified 129 Disc1 allele. It remains unclear what are the molecular, developmental, and behavioral consequences of the native 129 deletion allele of Disc1. Also, it remains uncertain to what extent this model and other transgenic overexpression models (Hikida et al., 2007; Pletnikov et al., 2008) “mimic” or “model” the molecular nature and phenotypic consequences of the SZ-associated human t(1;11) translocation. The original report suggested no brain morphological differences from wild-type, but more careful and detailed examination now reveals localized abnormalities, notably in the organization of newly born and mature neurons in the dentate gyrus. These results both resonate with and somewhat contradict earlier reports (Kamiya et al., 2005; Duan et al., 2007) that RNAi-mediated downregulation of Disc1 leads to abnormal neuronal migration and integration. Most likely, these differences reflect experimental differences (lifetime vs. transient downregulation of Disc1; cell autonomous vs. field effects). These issues will only be resolved by further study for which the availability of inducible transgenic models (Pletnikov et al., 2008; Li et al., 2007) will prove valuable.

The subtle neurodevelopmental abnormalities reported by Kvajo et al. (2008) were accompanied by abnormal short-term (but not long-term) potentiation in CA3CA1 synapses. Behavioral tests confirmed the previous report of a selective impairment of working memory. To conclude, this latest report adds to the rich evidence base that in the mouse Disc1 plays a crucial, if subtle neurodevelopmental role, which impacts on working memory. Taken alongside the other mouse models now available and others waiting in the wings, the field of SZ research can but benefit from their availability and the capacity they bring to construct and test hypotheses not possible in cell-based systems or ethically acceptable in human subjects. It is now timely and possible to explore and integrate in fine detail the neurodevelopmental, behavioral, neurophysiological, and pharmacological aspects of these models for what that may tell us about SZ. Importantly, with these various models to hand, it is also possible to examine fetal programming, epigenetic and environmental hypotheses predicted to exacerbate (or protect against) the neurodevelopmental and cognitive antecedents of SZ and their correlates in the mouse.


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

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, 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

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. 2008 Feb 1;13(2):173-86, 115. 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

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

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 David J. PorteousComment by:  Akira Sawa, SRF Advisor
Submitted 16 May 2008
Posted 16 May 2008

A leading group studying DISC1, led by Drs. Gogos and Karayiogou, has recently published an intriguing paper on further characterization of mice with genetic mutation/modulation in the Disc1 gene (first described in Koike et al., 2006). I would like to applaud their outstanding and detailed analyses in the manuscript, which obviously provides great benefits to the field. The methodologies that this group employed in this paper would be useful for future studies in modeling mice for psychiatric disorders. However, there are a couple of points in the descriptions in the Discussion section which I would like to comment on for a general audience.

First, isoform disposition of DISC1 is very complex. As Dr. Barbara Lipska has presented in academic conferences from her studies, there seem to be many more DISC1 isoforms than we predicted. Thus, unless one makes knockout mice in which the deleted region of the genome is clearly demonstrated by experimental data, we cannot draw any conclusion on whether or not the mice have no major allele(s) of Disc1. In this sense, although it is obvious that the mice presented in this manuscript are useful and beneficial for the basic understanding of DISC1, it is totally unclear whether or not major Disc1 isoforms are depleted in the mice reported in this manuscript. There is, in contrast, a published paper in which many laboratories tested their own “self-made” antibodies, the specificity of which was very carefully controlled in 129 and B6 mice (Ishizuka et al., 2007). More extensive comparison of Disc1-related reagents and mice among researchers will facilitate the progress of this field.

Second, the authors cited the paper by Kamiya et al. (Kamiya et al., 2005) incorrectly. The collaborative team among Pletnikov's, Song's, and our labs proposes that knockdown expression of Disc1 in the developing cortex leads to delayed migration, compared with accelerated migration in adult dentate gyrus (Duan et al., 2007). As Kamiya’s study utilized shRNA against exons 6 and 10, whereas Song/Duan’s study used shRNA against exon 2, we cannot fully exclude the possibility that the differences are coming from isoform-specific effects. This collaborative team at Johns Hopkins is currently addressing roles for DISC1 in several contexts of neurodevelopment in a systematic manner, including trials of shRNA targeting different portions of Disc1 (probably targeting different isoforms of Disc1) to various neurodevelopmental contexts, such as developing cerebral cortex and adult dentate gyrus. Because the mice presented in this paper depleted some, but not all, major isoforms, the phenotypic differences should be discussed in regional/context/isoform-specific manners. Nonetheless, the overall contribution of this paper is a great one for the field.


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

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 Akira Sawa

Comments on Related News

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

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

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

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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