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

View all comments by Anil Malhotra

PDE 4B enzyme activity is increased by PKA activation, hence, the suggested use of PDE inhibitors (like rolipram) in schizophrenia. I have another suggestion, especially because rolipram has unacceptable side-effects. Lauren Marangell's group in Texas (Mirnikjoo et al., 2001) has found that long-chain omega-3 essential fatty acids inhibit several protein kinases, including PKA.

Not only does this observation suggest one mechanism for the suggested benefits of omega-3 treatment of schizophrenia, but it also makes one wonder about the role of dietary omega-3 deficiency in causing or aggravating schizophrenia, especially during gestation, infancy, childhood, and adolescence, when unregulated PDE 4B activity could gravely affect neural development, contributing to schizophrenia pathogenesis.

Such deficiency may have begun, in industrial Western populations, when national fish consumption began to decline during the nineteenth century. Schizophrenia patients—and their mothers—in...  Read more

View all comments by Robert Peers

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

Response to comment by Angus Nairn
Thanks for your comment, Angus. With respect to the model proposed in our paper (Millar et al., 2005), perhaps it wasn't clear enough. However, the model proposed in this study envisages that DISC1 sequesters PDE4B in a "low(er) activity state," and most definitely not in an inactive state. Then it is suggested that activation of PKA by elevated cAMP levels allows, in these differentiated cells, for the release of PKA phosphorylated PDE4B in a "high(er) activity state." Interaction with DISC1 does not affect per se the activity of PDE4B in our hands. PDE4B does not need to be phosphorylated by PKA to be active (see, e.g., MacKenzie et al., 2002).

Note that PDE4 isoforms play a key role in underpinning compartmentalized cAMP signaling through interacting with distinct proteins in cells (Baillie et al., 2005;   Read more

View all comments by Miles Houslay

I found the paper by Kholmanskikh and colleagues, which proposes a novel role for LIS1 in neuronal motility by bridging calcium signaling to Cdc42, of great interest for schizophrenia research. LIS1 was originally identified as the causative gene for lissencephaly, but cascades that include LIS1 may have implications for schizophrenia. Several groups, including ours, have reported that a candidate gene product for schizophrenia, DISC1, forms a protein complex with LIS1 (Brandon et al., 2004; Kamiya et al., 2005).

My collaborators, Brian Kirkpatrick and Rosy Roberts, have observed and presented data that DISC1 immunoreactivity is enriched in some (but not all) of the postsynaptic densities, where Rho-family GTPases, such as Cdc42, also occur and regulate synaptic functions (Society for Neuroscience Meeting, 2004). Many of us agree that schizophrenia is, at least in part, a disorder of synapses. Taken all...  Read more

View all comments by Akira Sawa

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

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

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

View all comments by J David Jentsch

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

View all comments by Kirsty Millar

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

View all comments by Akira Sawa

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

View all comments by Luiz Miguel Camargo

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

View all comments by Joseph Friedman

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

View all comments by David J. Porteous
View all comments by Kirsty Millar

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

View all comments by John Roder

Several recent studies on disruptions of the DISC1 gene in mice illustrate the great potential of genetic approaches to studying functions of putative schizophrenia susceptibility genes but also signal the complexity of the problem. An initial rationale for studying the effects of mutations in DISC1 came from the discovery of the chromosomal translocation, resulting in a breakpoint in the DISC1 gene that co-segregated with major mental illness in a Scottish family (reviewed by Porteous et al., 2006). These clinical findings were followed by a number of association studies, which reported that numerous SNPs across the gene were associated with schizophrenia and mood disorders and a variety of intermediate phenotypes, suggesting that other problems in the DISC1 gene may exist in other subjects/populations.

Recent animal models designed to mimic partial loss of DISC1 function suggested that DISC1 is necessary to support development of the cerebral cortex as its loss resulted in impaired neurite...  Read more

View all comments by Barbara K. Lipska

I am very glad that our colleagues at Johns Hopkins University have published a very intriguing paper in Cell, showing a novel role for DISC1 in adult hippocampus. This is very consistent with previous publications (Miyoshi et al., 2003; Kamiya et al., 2005; and others; reviewed by Ishizuka et al., 2006), and adds a new insight into a key role for DISC1 during neurodevelopment. In short, DISC1 is a very important regulator in various phases of neurodevelopment, which is reinforced in this study. Specifically, DISC1 is crucial for regulating neuronal migration and dendritic development—for acceleration in the developing cerebral cortex, and for braking in the adult hippocampus.

There is precedence for signaling molecules playing the same role in different contexts, with the resulting molecular activity going in different directions. For example, FOXO3 (a member of the Forkhead transcription factor family) plays a role in...  Read more

View all comments by Akira Sawa

Recent findings, including the interactome study by Camargo et al., 2007, and this beautiful study by Duan and colleagues, implicate DISC1 (a leading candidate schizophrenia susceptibility gene) in synaptic function, consistent with prevailing ideas of the disorder as one of the synapse and connectivity (see Stephan et al., 2006). As we learn more about DISC1 and its protein partners, evidence demonstrating the importance of microtubules in the regulation of several neuronal processes (see Eastwood et al., 2006, for review) suggests that DISC1’s interactions with microtubule associated proteins (MAPs) may underpin its pathogenic influence.

DISC1 has been shown to bind to several MAPs (e.g., MAP1A, MIPT3) and other proteins important in regulating microtubule function (see Kamiya et al., 2005; Porteous et al., 2006). As a key component of the cell...  Read more

View all comments by Sharon Eastwood

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

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

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

View all comments by John Roder
View all comments by Steven Clapcote

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...  Read more

View all comments by Jill Morris
View all comments by Kate Meyer

Mao and colleagues present an impressive body of work implicating GSK3β/β-catenin signaling in the function of Disc1. However, several key experimental controls are missing that detract from the impact of their study, and it is unclear whether this function of Disc1 among its many others is the critical link between the t(1;11) translocation and psychopathology in the Scottish family.

The results of Mao et al. suggest that acute knockdown of Disc1 in embryonic brain causes premature exit from the proliferative cell cycle and premature differentiation into neurons. In fact, they observe fewer GFP+ cells in the VZ/SVZ and greater GFP+ cells within the cortical plate. This is in contrast to the study by Kamiya et al. (2005), in which they find that knocking down Disc1 caused greater retention of cells in the VZ/SVZ and fewer in the cortical plate, suggesting retarded migration. Although the timing of electroporation (E13 vs. E14.5) and examination (E15 vs. P2) differed between the two studies, these results are not...  Read more

View all comments by Khaled Rahman

This is an intriguing paper that builds on a growing body of evidence implicating wnt regulation of GSK3 signaling in psychotic illness (Lovestone et al., 2007).

It is interesting that the authors report that binding of DISC1 to GSK3 results in no change in the inhibitory Ser9 phosphorylation site of GSK3 but a change in Y216 activation site and that this resulted in effects on some but not all GSK3 substrates. This poses a challenge both in terms of understanding the role of GSK3 signaling in schizophrenia and other psychotic disorders and in drug discovery.

The authors cite some of the other evidence for regulation of GSK3 signaling in psychosis, including, for example, the evidence for a role of AKT signaling alteration in schizophrenia and lithium, an inhibitor of GSK3, as a treatment for bipolar disorder. But in both cases, AKT (Cross et al., 1995) and lithium (Jope, 2003), the effect on GSK3 is predominantly via Ser9...  Read more

View all comments by Simon Lovestone

Li-huei Tsai and colleagues have identified another pathway in which the candidate gene DISC1 looks to have a critical regulatory role, namely the wnt signaling pathway, in progenitor cell proliferation. In recent years we have seen that DISC1 has a vital role at the centrosome (Kamiya et al., 2005), in cAMP signaling (Millar et al., 2005), and in multiple steps of adult hippocampal neurogenesis (Duan et al., 2007). They have shown a pivotal role for DISC1 in neural progenitor cell proliferation through regulation of GSK3 signaling using a spectacular combination of cellular and in utero manipulations with shRNAs and GSK3 inhibitor compounds. These findings clearly implicate DISC1 in another “druggable” pathway but at this stage do not really identify new approach/targets, except perhaps to confirm that manipulating adult neurogenesis and the wnt pathway holds much potential hope for therapeutics. Perhaps understanding the mechanism of...  Read more

View all comments by Nick Brandon

Mao and colleagues’ present outstanding work sheds light on a novel function of DISC1. Because DISC1 is a multifunctional protein, the addition of new functions is not surprising. Thus, for the past several years, the field has focused on how DISC1 can have distinct functions in different cell contexts (for example, progenitor cells vs. postmitotic neurons, or developing cortex vs. adult dentate gyrus). In addition to Mao and colleagues, I understand that several groups, including ours, have obtained preliminary, unpublished evidence that DISC1 regulates progenitor cell proliferation, at least in part via GSK3β. Thus, I am very supportive of this new observation.

If there might be a missing point in this paper, it is unclear whether suppression of GSK3β occurs in several different biological contexts in brain in vivo. In other words, it is uncertain whether DISC1’s actions on GSK3β are constitutive or context-dependent. How can we reconcile differential roles for DISC1 in progenitor cells in contrast to postmitotic neurons? We have already obtained a...  Read more

View all comments by Akira Sawa

This is a really interesting study, which should stimulate new thinking and experimentation. cAMP-dependent signaling is a core component of the mammalian circadian pacemaker (O'Neill et al., 2008). Do those schizophrenic (and indeed non-schizophrenic) patients with sleep disorder show direct evidence for altered PDE4 signaling? If so, does genetic variation in the DISC1-PDE4 complex contribute to this and indicate a differential molecular diagnosis? Clapcote et al. (2007) reported differential effects of Disc1 missense mutations Q31L and L100P on brain PDE4 activity and on behavioral response to rolipram. Do these strains and indeed other Disc1 mutant mice have disturbed sleep patterns?

References:

O'Neill JS, Maywood ES, Chesham JE, Takahashi JS, Hastings MH. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science . 2008 May 16 ; 320(5878):949-53. 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

View all comments by David J. Porteous

Although disturbed sleep is a prominent feature of schizophrenia that has been recognized since Kraepelin (1919), its relation to the pathophysiology, signs, and symptoms of schizophrenia remains poorly understood. In healthy individuals, there is now overwhelming evidence that critical aspects of learning and memory consolidation depend on sleep. Yet, in spite of the ubiquity of sleep disorders in schizophrenia, they have generally been overlooked as a potential contributor to cognitive deficits. As recently reviewed by Manoach and Stickgold (2009), an emerging literature suggests that abnormal sleep in schizophrenia may contribute to these cognitive deficits through its impairment of sleep-dependent memory consolidation.

The finding by Vecsey et al. that sleep deprivation leads to an increase in transcription and translation of the gene coding for phosphodiesterase-4 (PDE4), and that inhibiting the action of PDE4 with the drug rolipram restores both normal cAMP levels and sleep-dependent memory consolidation in rodents,...  Read more

View all comments by Robert Stickgold
View all comments by Dara Manoach