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 (  Read more

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.

References:

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

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...  Read more

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.

References:

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

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 (  Read more

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 (http://www.informatics.jax.org/external/festing/mouse/docs/129.shtml). 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 (http://www.informatics.jax.org/external/festing/mouse/docs/C57BL.shtml). 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.

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...  Read more

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.

References:
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).

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

Cognitive symptoms have emerged as an independent feature of schizophrenia that needs to be targeted for treatment independent of more well-known symptoms such as hallucinations and delusions. Indeed, the level of impairment in cognitive abilities is one of the strongest predictors of impaired adaptive life skills in patients with schizophrenia. The prefrontal cortex, critical for cognitive abilities such as working memory and executive functions, is well established to be dysfunctional in patients with schizophrenia. Although the significance of dopamine-related changes to the prefrontal cortex in schizophrenia has been extensively studied, noradrenergic changes are also important, but often overlooked. Moreover, second-generation antipsychotics, which partially address the reduced prefrontal dopamine activity in patients with schizophrenia, have only modest effects on the cognitive impairments associated with schizophrenia.

Alpha-2 noradrenergic agonists, such as the antihypertensive drug guanfacine, increase noradrenergic activity in the prefrontal cortex. Evidence...  Read more

Cognitive symptoms have emerged as an independent feature of schizophrenia that needs to be targeted for treatment independent of more well-known symptoms such as hallucinations and delusions. Indeed, the level of impairment in cognitive abilities is one of the strongest predictors of impaired adaptive life skills in patients with schizophrenia. The prefrontal cortex, critical for cognitive abilities such as working memory and executive functions, is well established to be dysfunctional in patients with schizophrenia. Although the significance of dopamine-related changes to the prefrontal cortex in schizophrenia has been extensively studied, noradrenergic changes are also important, but often overlooked. Moreover, second-generation antipsychotics, which partially address the reduced prefrontal dopamine activity in patients with schizophrenia, have only modest effects on the cognitive impairments associated with schizophrenia.

Alpha-2 noradrenergic agonists, such as the antihypertensive drug guanfacine, increase noradrenergic activity in the prefrontal cortex. Evidence demonstrating cognitive-enhancing effects of guanfacine on cognitive abilities related to the prefrontal cortex in both animals and healthy human subjects suggests a potential role for guanfacine in treating some of the cognitive impairments of schizophrenia. Although limited, there is some evidence in support of cognitive enhancing effects of guanfacine in patients with schizophrenia (Friedman et al., 2001). Our current clinical trial seeks to determine the reproducibility of these preliminary results and assess the potential effects of guanfacine on the adaptive life skills of patients with schizophrenia. This study is being conducted in the New York State Mental Health System, specifically at Pilgrim Psychiatric Center (Mount Sinai Hospital is the sponsor) and at the Bronx Veterans Administration Medical Center (the sponsor is the VISN3 MIRECC). We expect results by end of year 2008.

Should guanfacine be effective, my plan would be to try to obtain federal funding for a larger multi-site study of guanfacine in combination with either a social skills or cognitive skills rehabilitation program. However, even if proven effective, it is important to keep in mind that any potential guanfacine effects will be limited to cognitive abilities associated with the prefrontal cortex. As data from animal models and healthy human subjects indicate, guanfacine will most likely be ineffective in addressing important cognitive symptoms related to temporal lobe changes in schizophrenia.

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...  Read more

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.

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...  Read more

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.

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,...  Read more

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.

References:

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

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...  Read more

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.

References:

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