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.

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

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.

Although DISC1 is multifunctional, its role for neurite outgrowth has been substantially characterized for the past couple of years (Ozeki et al., 2003; Miyoshi et al., 2003; Kamiya et al., 2006). These studies indicated that DISC1 is involved in neurite outgrowth by more than one mechanism, such as interactions with NUDEL/NDEL1 and FEZ1.

These two papers from Kaibuchi’s lab provide further understanding of how DISC1 is involved in neuronal outgrowth. Kaibuchi’s group identified kinesin heavy chain of kinesin-1 as a novel interactor of DISC1. In their papers, a novel role for DISC1, to link kinesin-1 (microtubule-dependent and plus-end directed motor) to several cellular molecules, including NUDEL, LIS1, 14-3-3, and Grb2, is reported. DISC1 and kinesin-1 are, therefore, responsible to sort Grb2 to the distal part of axons where Grb2...  Read more

Although DISC1 is multifunctional, its role for neurite outgrowth has been substantially characterized for the past couple of years (Ozeki et al., 2003; Miyoshi et al., 2003; Kamiya et al., 2006). These studies indicated that DISC1 is involved in neurite outgrowth by more than one mechanism, such as interactions with NUDEL/NDEL1 and FEZ1.

These two papers from Kaibuchi’s lab provide further understanding of how DISC1 is involved in neuronal outgrowth. Kaibuchi’s group identified kinesin heavy chain of kinesin-1 as a novel interactor of DISC1. In their papers, a novel role for DISC1, to link kinesin-1 (microtubule-dependent and plus-end directed motor) to several cellular molecules, including NUDEL, LIS1, 14-3-3, and Grb2, is reported. DISC1 and kinesin-1 are, therefore, responsible to sort Grb2 to the distal part of axons where Grb2 functions as an adaptor and plays a role in NT-3-induced phosphorylation of ERK1/2. This mechanism well explains our previous work, led by Ryota Hashimoto, reporting that knockdown of DISC1 expression results in decreased levels of phosphorylation of ERK1/2 and Akt in primary cortical neurons (Hashimoto et al., 2006).

The interaction of DISC1 and kinesin-1 may also be interesting from the perspective of psychiatric genetics. First, the mechanism proposed in one of the papers (Taya et al., 2007) supports the notion that the C-terminal truncated DISC1 fragment—that occurs due to the balanced translocation in an extended Scottish family—functions as a dominant-negative. Second, the domain of DISC1 responsible for kinesin-1 is overlapped with the haplotype block region(s) that are positive in more than one association study of DISC1 and major mental illnesses.

Two recent back-to-back papers, published this month in Journal of Neuroscience, highlight the value of protein-protein interactions in determining the biological role of a key schizophrenia risk factor, DISC1, in processes that are important for the proper development of neurons.

Key questions need to be addressed once having established a set of interactors for a given protein. First, where do these proteins interact on the target molecule? Second, do these interactions take place at the same time (i.e., do they form a complex)? Third, in what context do these interactions occur (temporal, tissue/cell compartment, signaling), and, fourth, are the biological processes of the interacting molecules affected/regulated by the protein of interest? The Kaibuchi lab, as exemplified in the works by Taya et al. and Shinoda et al., elegantly address some of these questions in the context of DISC1 interactions with Grb2, Nudel (NDEL1), 14-3-3ε, and kinesin-1. The key findings of these papers are as follows:

1. Identification of the interaction sites, or more importantly,...  Read more

Two recent back-to-back papers, published this month in Journal of Neuroscience, highlight the value of protein-protein interactions in determining the biological role of a key schizophrenia risk factor, DISC1, in processes that are important for the proper development of neurons.

Key questions need to be addressed once having established a set of interactors for a given protein. First, where do these proteins interact on the target molecule? Second, do these interactions take place at the same time (i.e., do they form a complex)? Third, in what context do these interactions occur (temporal, tissue/cell compartment, signaling), and, fourth, are the biological processes of the interacting molecules affected/regulated by the protein of interest? The Kaibuchi lab, as exemplified in the works by Taya et al. and Shinoda et al., elegantly address some of these questions in the context of DISC1 interactions with Grb2, Nudel (NDEL1), 14-3-3ε, and kinesin-1. The key findings of these papers are as follows:

1. Identification of the interaction sites, or more importantly, which part of DISC1 is involved in particular processes, for example, that axon elongation is dependent on the N-terminal, but not the C-terminal portion of DISC1. This suggests that the DISC1 role in axon elongation is mediated by interactions with the N-terminal portion of DISC1 that could be competed for by the truncated protein in a dominant negative fashion (Camargo et al., 2007).

2. Although a protein may have many interacting partners, such as DISC1, these interactions may not occur at the same time. For example, DISC1 is able to form a ternary complex with kinesin-1 and NDEL1 or with kinesin-1 and Grb2. However, a ternary complex of DISC1-Grb2-NDEL1 is not possible as Grb2 and NDEL1 may be competing for the same interaction site on DISC1.

3. Protein interactions may occur in certain cellular compartments, in the case of DISC1, the cell body and the distal part of axons.

4. Neurotrophin-induced axon elongation requires DISC1.

These papers confirm some of the hypotheses raised by the interactions that we have recently derived for DISC1 and some of its interacting partners (see Camargo et al., 2007). From the DISC1 interactome, we concluded that DISC1 may affect key intracellular transport mechanisms, such as those regulated by kinesins, and that DISC1 may be downstream of neurotrophin receptors, via its interaction with SH3BP5, an adaptor protein, which we found to interact with SOS1, a guanine exchange factor that binds Grb2 and responds to signaling of neurotrophin receptors. These observations have been validated by Taya et al. and Shinoda et al. and demonstrate the value of the DISC1 interactome in understanding the role of DISC1, and as a valuable resource to the wider community.

The molecular function of DISC1, as defined by its structure, still remains elusive, requiring a more dedicated effort on this front. The good news is that, via its protein-protein interactions, significant progress on the role of DISC1 in key biological processes has been achieved, as illustrated by the work of different labs (Brandon et. al., 2004; Millar et al., 2005; Kamiya et al., 2005; and now by Shinoda et al. and Taya et al.).

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

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

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

Although we need...  Read more

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.

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

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

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

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.

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

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

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.