Schizophrenia Research Forum - A Catalyst for Creative Thinking

DISC1 Players Gird For Adult Neurodevelopment

8 October 2009. DISC1, or disrupted-in-schizophrenia 1, is a major candidate gene for schizophrenia and other major psychiatric disorders such as bipolar disorder. Scientists are only beginning to come to grips with the properties of DISC1, and with how the gene relates to pathology. Two recent papers may help. Researchers in Japan report that DISC1 interacts with girdin, a protein that binds to the cytoskeletal protein actin. The researchers found that the DISC1-girdin interplay helps regulate development of neuronal axons in the postnatal hippocampus, a major birthplace for new neurons in the adult brain. In a second article, researchers in the U.S. report that DISC1 helps drive formation of new neurons, also in the adult hippocampus, by attenuating the activity of the protein Akt. That kinase regulates a plethora of processes in neurons, including developmental pathways. The researchers show that DISC1 suppresses Akt by sequestering a protein called KIAA1212, which is another name for none other than…girdin.

Together, the two papers highlight girdin as a major DISC1 player and add to the growing evidence that DISC1 plays a significant role in postnatal neurogenesis. Since the Akt gene has also been linked to risk for schizophrenia and other brain disorders, such as autism and bipolar disorder (see SRF related news story), the research also hints that the DISC1/Akt pathway may be pivotal to psychiatric disorders. The papers, which appeared in the September 24 Neuron, “add more detail to the complex picture of the biochemical interactions of DISC1 and its diverse cellular functions,” wrote Kevin Mitchell, Trinity College Dublin, Ireland, in a comment to SRF (see below).

Akt 1, Scene 1
Senior author Guo-li Ming and colleagues at Johns Hopkins University, Baltimore, Maryland, explored the relation between DISC1 and Akt kinase because cells lacking the former behave very similarly to those lacking PTEN, a protein that counteracts Akt. That similarity suggested that DISC1 might suppress Akt, and, in fact, first author Ju Young Kim and colleagues found that knocking down DISC1 led to increased Akt activity in mouse newborn neurons. The researchers found that DISC1 binds to KIAA1212, a protein known to promote activation of Akt in cells. After a series of experiments to test protein-protein interactions, the researchers concluded that DISC1 suppresses Akt signaling by preventing KIAA1212, i.e., girdin, from activating the kinase.

The suppression of Akt has important consequences for the development of newborn neurons in the adult brain. The researchers found that knocking down DISC1 or PTEN, or overexpressing girdin or a constitutively active form of Akt, all led to increases in the size of neuron cell bodies and an accelerated growth and increase in number of dendrites. Newborn neurons in the adult hippocampus also tended to migrate farther than usual, beyond the granule layer and into the molecular layer, when Akt suppression was relieved by knocking down DISC1 or PTEN. The results indicated that DISC1 can regulate morphogenesis and migration of new neurons in the adult hippocampus.

What are the downstream events that mediated these responses? Akt has many substrates but Kim and colleagues found that signaling via mTOR, or mammalian target of rapamycin, plays a key role. When they suppressed DISC1 expression, mTOR signaling increased, and they were also able to rescue the effects of knocking down DISC1 in cells by adding rapamycin.

Girdin, Supporting Actor
For their part, the Japanese researchers, led by Atsushi Enomoto and Masahide Takahashi at Nagoya University, focused on girdin (girders of actin filaments) because it was previously shown to bind DISC1 and another DISC1 partner, Nudel (see Camargo et al., 2007 and SRF related news story). Enomoto and colleagues found that girdin is expressed in the mouse hippocampus by postnatal day 15, predominantly in neurons rather than neural stem cells, and mostly in the dentate granule cell layer. Because the pattern and timing of girdin expression overlaps with that of DISC1, the researchers speculated that the two proteins cooperate to regulate the development and function of neurons in the dentate gyrus of the hippocampus.

Enomoto and colleagues found that girdin is essential for the development of new neurons. After about two days in culture, rat hippocampal cells begin to polarize, developing a single long outgrowth that becomes a growing axon. This process was blocked when girdin expression was silenced by short-hairpin RNAs. The researchers also found that axon extension was severely impaired in neurons isolated from girdin-negative mice. Girdin-mediated axon growth also seems to depend on DISC1. The proteins colocalize at axonal growth cones, but in the absence of DISC1, girdin levels at growth cones was significantly reduced. The authors suggest that the role of DISC1 may be to stabilize and/or anchor girdin at those growth cones.

In vivo, girdin seems essential for the proper organization of hippocampal architecture. In girdin-negative mice, the granule cell layer of the hippocampus is sparsely populated and the CA1 region of the hippocampus consists of multilayers rather than a single layer. Mossy fibers, axons that extend from the dentate granule cells, were also severely underdeveloped in girdin-negative mice. These observations are consistent with defects in neuronal migration, which is in keeping with the findings from the Ming group and also with previous work showing that DISC1 regulates the migration and integration of newborn neurons in the hippocampus (see SRF related news story). In fact, similar to findings from Ming’s group, Enomoto and colleagues went on to show that in girdin-negative mice, newborn neurons of the dentate gyrus migrated to all levels of the granule cell layer and even the molecular layer, rather than being contained to the inner third of the granule cell layer.

What role does DISC1 play in girdin-mediated cell migration? The researchers tested this using a girdin N-terminal (NT) domain, the part of the molecule that binds to DISC1. Just the NT domain competes with the full-length girdin for DISC1 in cells, and when the authors introduced the NT domain into the hippocampus of postnatal day 5 rats, it caused similar cell migration problems to those seen in girdin-negative mice. Furthermore, they could not rescue the effects of silencing girdin expression with DISC1, indicating that girdin lies downstream of DISC1 in any signaling cascade. The researchers found that girdin lies downstream of Akt as well, because a dominant active form of the kinase also failed to rescue the effects of girdin silencing.

As noted in a Neuron Preview by David Porteous and Kirsty Millar from Edinburgh University, the two studies have some areas of disagreement. While Enomoto and colleagues’ observations suggest girdin suppression mimics loss of DISC1 in adult progenitor cells, including migratory and integration problems (see SRF related news story), Kim and colleagues report that girdin overexpression mimics DISC1 suppression. Porteous and Millar suggest that “…this perhaps indicates that both the balance of DISC1 interactome expression and the resultant stoichiometry of interactors, as well as the precise developmental timing of expression, is important.” The discrepancies may also relate to the fact that girdin seems to act as both an activator of Akt and an Akt substrate.

Full Cast
These studies highlight, yet again, the role of DISC1 in biological pathways that control neurodevelopment (see SRF related news story and SRF related news story). In addition to DISC1, Akt, and PTEN, other proteins that interact with DISC1 and play important roles in neurodevelopment have been implicated in schizophrenia, including neuregulin (see SRF related news story) and the ErbB4 receptor (see SRF related news story). DISC1 also suppresses another kinase, GSK3β While the GSK3β inhibitor SB216763 rescues effects of DISC1 suppression on neural progenitors (see SRF related news story), Kim and colleagues found that the compound had no effect on aberrant morphology, including dendritic expansion, of new neurons lacking DISC1. “When all the evidence is taken together, we now have a tantalizing picture of how DISC1, through Akt, GSK3β, and other protein partners yet to be fully described, may regulate both neurodevelopment and neurotransmission, two core yet often opposed concepts in schizophrenia etiology,” write Porteous and Millar.

Whether any of this will help uncover new treatments for schizophrenia remains to be seen. Though rapamycin can rescue aspects of DISC1 suppression, it is also a potent immunosuppressant and might not be suitable as a chronic treatment. If the effects of rapamycin and SB216763 are positive portents of future therapeutic strategies, write Porteous and Millar, “it will nevertheless be critical to determine exactly which aspects of the DISC1 pathway phenotype must be corrected, and when, during brain development.”—Tom Fagan.

Kim JY, Duan X, Liu CY, Jang M-H, Guo JU, Pow-anpongkul N, Kang E, Song H, Ming G-L. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron. 2009 September 24; 63:761-773. Abstract

Enomoto A, Asai N, Namba T, Wang Y, Kato T, Tanaka M, Tatsumi H, Taya S, Tsuboi D, Kuroda K, Kaneko N, Sawamoto K, Miyamoto R, Jijiwa M, Murakomo Y, Sokabe M, Seki T, Kaibuchi K, Takahashi M. Roles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus. Neuron. 2009 September 24; 63: 774-787. Abstract

Comments on News and Primary Papers
Comment by:  Kevin J. Mitchell
Submitted 8 October 2009
Posted 8 October 2009

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

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

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

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

View all comments by Kevin J. MitchellComment by:  Peter PenzesMichael Cahill
Submitted 8 October 2009
Posted 8 October 2009

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

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

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


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

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

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

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

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

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

View all comments by Peter Penzes
View all comments by Michael Cahill

Comments on Related News

Related News: Playing on Without AKT1: Subtle Cortical Deficits Suggest Vulnerabilities

Comment by:  Takeo YoshikawaAkihiko Takashima
Submitted 30 November 2006
Posted 30 November 2006
  I recommend the Primary Papers

In this study, Karayiorgou and Gogos’s group have conducted a meticulous anatomical analysis of pyramidal cell dendritic structures in the prefrontal layer V cortex, as well as genome-wide expression and pharmaco-behavioral analyses, focusing on prefrontal functions in Akt1-deficient mice. The study examines the reduced (or altered) AKT1-GSK3β signalling theory of schizophrenia, proposed by this (Emamian et al., 2004) and other groups.

AKT1 as a genetic susceptibility gene for schizophrenia shows promise in the Caucasian population but this is not reflected in Asian populations as evidenced by our results (Ide et al., 2006). In addition, even in Caucasians, true causal variants have not been identified. Because of this, schizophrenia researchers are interested in observing disease-relevant phenotypes in Akt1-deficient mice. In this study, they have detected morphological and functional alterations of frontal cortex-related traits in mutant mice using state-of-the-art techniques.

To further strengthen AKT1 as a candidate disease gene in schizophrenia, several issues need to be addressed in the near future. For instance, if a reduction of AKT1 signalling occurs in the brain, tau should be hyper-phosphorylated by activated GSK3β, which in turn will lead to the formation of neurofibrillary tangles (NFTs) as seen in Alzheimer’s disease. Therefore, it would be interesting to determine whether Akt1-deficient mice show a similar pattern of tau phosphorylation. Accumulating evidence suggests that hyper-phosphorylated tau may affect a variety of neuronal functions. Our recent biochemical analyses failed to reveal any significant reduction of AKT-mediated signalling in the prefrontal cortex of schizophrenic brains or the expected inverse correlation between phosphorylation levels of AKT and tau (Ide et al., 2006). This highlights the difficulty of examining protein phosphorylation status using postmortem brains, where results are often confounded by multiple, uncontrollable factors.

Another important but poorly understood point is the functional relationship among subspecies of the AKT family (at least AKT1, AKT2 and AKT3) and GSK3 (GSK3α and GSK3β) (for example see Sale et al., 2005). We look forward to continuing multidisciplinary studies aimed at unravelling the role of the AKT cascade, including the clarification of downstream pathways (Datta et al., 1999; (O’Mahony et al., 2006) in schizophrenia pathology.

View all comments by Takeo Yoshikawa
View all comments by Akihiko Takashima

Related News: Neuregulin and Schizophrenia—Functional Failure Fingers Risk Allele

Comment by:  Ali Mohamad Shariaty
Submitted 14 July 2007
Posted 14 July 2007

It is really a fascinating article which is a step towards understanding the molecular mechanisms underlying phenotypes of schizophrenia. Relating genotypes to phenotypes is really necessary for untangling the puzzle of a complex disorder. However, when a regulatory SNP interferes with normal binding of a transcription factor, is it understood that the transcription factor should play a role in brain and therefore in the molecular pathology of schizophrenia? Is there any direct role for involvement of serum response factor (SRF) in brain development or any neurological process?

View all comments by Ali Mohamad Shariaty

Related News: Neuregulin and Schizophrenia—Functional Failure Fingers Risk Allele

Comment by:  Amanda Jayne Law, SRF Advisor
Submitted 14 July 2007
Posted 15 July 2007

In response to Ali Mohamad Shariaty’s comment: Serum response factor (SRF) plays a key role in regulating the transcription of a number of genes involved in brain development. Genetic manipulation of SRF has revealed a direct role for it as a regulator of cortical and hippocampal function (e.g., Etkin et al., 2006) influencing both learning and memory. At the cellular level SRF has been shown to regulate dendritic morphology and neuronal migration. Therefore, SRF is indeed an important neurodevelopmental molecule, mediated via its regulation of genes, such as NRG1. Genetic variations that are predicted to interfere with SRF binding (such as the SNP characterized in our study) may affect critical aspects of brain development and function that contribute to schizophrenia. Since SRF regulates the expression of a number of genes, beyond that of NRG1, its involvement in schizophrenia is likely mediated “indirectly” via its effects on the regulation of genes associated with the disorder.


Etkin A, Alarcón JM, Weisberg SP, Touzani K, Huang YY, Nordheim A, Kandel ER. A role in learning for SRF: deletion in the adult forebrain disrupts LTD and the formation of an immediate memory of a novel context. Neuron. 2006 Apr 6;50(1):127-43. Abstract

View all comments by Amanda Jayne Law

Related News: Neuregulin and Schizophrenia—Functional Failure Fingers Risk Allele

Comment by:  Robert Hunter
Submitted 17 July 2007
Posted 17 July 2007
  I recommend the Primary Papers

Related News: Modeling Schizophrenia Phenotypes—DISC1 Transgenic Mouse Debuts

Comment by:  David J. Porteous, SRF AdvisorKirsty Millar
Submitted 2 August 2007
Posted 2 August 2007

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

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

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

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

Related News: Modeling Schizophrenia Phenotypes—DISC1 Transgenic Mouse Debuts

Comment by:  John Roder
Submitted 2 August 2007
Posted 2 August 2007

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

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

View all comments by John Roder

Related News: DISC1: A Maestro of Adult Hippocampal Neurogenesis?

Comment by:  Barbara K. Lipska
Submitted 9 September 2007
Posted 9 September 2007

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 outgrowth and the spectrum of behavioral abnormalities characteristic of major mental disorders ( Kamiya et al., 2005; Koike et al., 2006; Clapcote et al., 2007; Hikida et al. 2007). Unexpectedly, however, the paper by Duan et al., 2007, is showing that DISC1 may also function as a brake and master regulator of neuronal development, and that its partial loss could lead to the opposite effects than previously described, i.e., dendritic overgrowth and accelerated synapse formation and faster maturation of newly generated neurons. In contrast to previous studies, they have used the DISC1 knockdown model achieved by RNA interference in a subpopulation of single cells of the dentate gyrus. Other emerging studies continue to reveal the highly complex nature of the DISC1 gene with multiple isoforms exhibiting different functions, perhaps depending on localization, timing, and interactions with a multitude of other genes’ products, some of which confer susceptibility to mental illness independent of DISC1. Similar molecular complexity has also emerged in other susceptibility genes for schizophrenia: GRM3 (Sartorius et al., 2006), NRG1 (Tan et al., 2007), and COMT (Tunbridge et al., 2007). With the growing knowledge about transcript complexity, it becomes increasingly clear that subtle disturbances of isoform(s) of susceptibility gene products and disruptions of intricate interactions between the susceptibility genes may account for the etiology of neuropsychiatric disorders. Research in animals will have a critical role in disentangling this web of interwoven genetic pathways.

View all comments by Barbara K. Lipska

Related News: DISC1: A Maestro of Adult Hippocampal Neurogenesis?

Comment by:  Akira Sawa, SRF Advisor
Submitted 13 September 2007
Posted 13 September 2007

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 cell survival/death in a bidirectional manner (Brunet et al., 2004). FOXO3 endows cells with resistance to oxidative stress in some contexts, and induces apoptosis in other contexts. SIRT1 (known as a key modulator of organismal lifespan) deacetylates FOXO3 and tips FOXO3-dependent responses away from apoptosis and toward stress resistance. In analogy to FOXO3, context-dependent post-translational modifications, such as phosphorylation, may be an underlying mechanism for DISC1 to function in a bidirectional manner. Indeed, a collaborative team at Johns Hopkins, including Pletnikov's lab, Song's lab, and ours, has started exploring, in both cell and animal models, the molecular switch that makes DISC1's effects bidirectional.


Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004 Mar 26;303(5666):2011-5. Abstract

View all comments by Akira Sawa

Related News: DISC1: A Maestro of Adult Hippocampal Neurogenesis?

Comment by:  Sharon Eastwood
Submitted 14 September 2007
Posted 14 September 2007

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 cytoskeleton, microtubules are involved in many cellular processes including mitosis, motility, vesicle transport, and morphology, and their dynamics are regulated by MAPs, which modulate microtubule polymerization, stability, and arrangement. Decreased microtubule stability in mutant mice for one MAP, stable tubule only polypeptide (STOP; MAP6), results in behavioral changes relevant to schizophrenia and altered synaptic protein expression (Andrieux et al., 2002; Eastwood et al., 2006), indicating the importance of microtubules in synaptic function and suggesting that they may be a molecular mechanism contributing to the pathogenesis of schizophrenia. Likewise, DISC1 mutant mice exhibit behavioral alterations characteristic of psychiatric disorders (e.g., Clapcote et al., 2007), and altered microtubule dynamics are thought to underlie perturbations in cerebral cortex development and neurite outgrowth caused by decreased DISC1 expression or that of a schizophrenia-associated DISC1 mutation (Kamiya et al., 2005).

Our interpretation of the possible functions of DISC1 has been complicated by the unexpected findings of Duan and colleagues that DISC1 downregulation during adult hippocampal neurogenesis leads to overextended neuronal migration and accelerated dendritic outgrowth and synaptic formation. In terms of neuronal positioning, they suggest that their results indicate that DISC1 may relay positional signals to the intracellular machinery, rather than directly mediate migration. In this way, decreased DISC1 expression may result in the mispositioning of newly formed neurons rather than a simple decrease or increase in their migratory distance. Of note, MAP1B, a neuron-specific MAP important in regulating microtubule stability and the crosstalk between microtubules and actin, is required for neurons to correctly respond to netrin 1 signaling during neuronal migration and axonal guidance (Del Rio et al., 2004), and DISC1 may function similarly during migration. Reconciling differences between the effect of decreased DISC1 expression upon neurite outgrowth during neurodevelopment and adult neurogenesis is more difficult, but could be due to differences in the complement of MAPs expressed by different neuronal populations at different times. Regardless, the results of Duan and colleagues have provided additional evidence implicating DISC1 in neuronal functions thought to go awry in schizophrenia. Further characterization of DISC1’s interactions with microtubules and MAPs may lead to a better understanding of the role of DISC1 in the pathogenesis of psychiatric disorders.


Andrieux A, Salin PA, Vernet M, Kujala P, Baratier J, Gory Faure S, Bosc C, Pointu H, Proietto D, Schweitzer A, Denarier E, Klumperman J, Job D (2002). The suppression of brain cold-stable microtubules in mice induces synaptic deficits associated with neuroleptic-sensitive behavioural disorders. Genes Dev. 16: 2350-2364. Abstract

Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S, Bonnert TP, Whiting PJ, Brandon NJ (2007). Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol. Psychiatry 12: 74-86. 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 (2007). Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54: 387-402. Abstract

Del Rio, J.A., Gonzalez-Billault, C., Urena, J.M., Jimenez, E.M., Barallobre, M.J., Pascual, M., Pujadas, L., Simo, S., La Torre, A., Wandosell, F., Avila, J. and Soriano, E. (2004). MAP1B is required for netrin 1 signaling in neuronal migration and axonal guidance. Cur. Biol. 14: 840-850. Abstract

Eastwood SL, Lyon L, George L, Andrieux A, Job D, Harrison PJ (2006). Altered expression of synaptic protein mRNAs in STOP (MAP6) mutant mice. J. Psychopharm. 21: 635-644. 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;7(12):1167-78. Epub 2005 Nov 20. Erratum in: Nat Cell Biol. 2006 Jan;8(1):100. Abstract

Porteous DJ, Thomson P, Brandon NJ, Millar JK (2006). The genetics and biology of DISC1-an emerging role in psychosis and cognition. Biol. Psychiatry 60: 123-131. Abstract

Stephan KE, Baldeweg T, Friston KJ (2006). Synaptic plasticity and disconnection in schizophrenia. Biol. Psychiatry 59: 929-939. Abstract

View all comments by Sharon Eastwood

Related News: DISC1: A Matter of Life or Death for Neural Progenitors

Comment by:  Khaled Rahman
Submitted 26 March 2009
Posted 26 March 2009

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 easily reconciled.

The authors also suggest that they can rescue the deficits in proliferation by overexpressing human wild-type DISC1, stabilizing β-catenin expression, or inhibiting GSK3β activity, and thus conclude that Disc1 is acting through this pathway. This conclusion, however, rests on an error in logic. If increasing X causes an increase in Y, and decreasing Z causes a decrease in Y, this does not mean that X and Z are operating via the same mechanism. In fact, overexpressing WT-DISC1, stabilizing β-catenin, or inhibiting GSK3β activity all increase proliferation in control cells. Thus, the fact that these manipulations also work in progenitors with Disc1 silenced only tells us that these effects are independent or downstream of Disc1. What are needed are studies that show a differential sensitivity of Disc1-silenced cells to manipulations of β-catenin or GSK3β. In other words, is there a shift in the dose response curves? This is what is to be expected given that Mao et al. show changes in β-catenin levels and changes in the phosphorylation of GSK3β substrates in Disc1 silenced cells.

Furthermore, it is surprising that a restricted silencing of Disc1 in the adult dentate gyrus produces changes in affective behaviors, when total ablation of dentate neurogenesis in the adult produces little effects on depression-related behaviors (Santarelli et al., 2003; Airen et al., 2007). The fact that inhibiting GSK3β increases proliferation in both control and Disc1 knockdown animals to a similar degree suggests that the “rescue” of any behavioral deficits is independent of the drug’s effects on proliferation. Correlating measures of proliferation with behavioral performance would help address this issue.

How this study will lead to new or improved therapeutic interventions is also an open question. Lithium is well known for its mood-stabilizing properties, and this study may point to better, more efficient ways to address these symptoms. However, it is also known that lithium does little for, if not worsens, cognitive symptoms in patients (Pachet and Wisniewski, 2003), and it is this symptom domain that is in dire need of drug development.

It is also important to keep in mind that acute silencing of Disc1 in a restricted set of cells will not necessarily recapitulate the pathogenetic process of a disease-associated mutation. It remains to be seen if similar results are obtained in animal models of the Disc1 mutation (Clapcote et al., 2007; Hikida et al., 2007; Li et al., 2007).


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

Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003). Abstract

Airan, R.D. et al. High-speed imaging reveals neurophysiological links to behavior in an animal model of depression. Science 317, 819-23 (2007). Abstract

Pachet AK, Wisniewski AM. The effects of lithium on cognition: an updated review. Psychopharmacology (Berl). 2003 Nov;170(3):225-34. Review. Abstract

Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, et al. (2007) Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54: 387–402. Abstract

Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, et al. (2007) Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A 104: 14501–14506. Abstract

Li W, Zhou Y, Jentsch JD, Brown RA, Tian X, et al. (2007) Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci U S A 104: 18280–18285. Abstract

View all comments by Khaled Rahman

Related News: DISC1: A Matter of Life or Death for Neural Progenitors

Comment by:  Simon Lovestone
Submitted 27 March 2009
Posted 27 March 2009

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 phosphorylation and not via Y216. The unstated implication is at least two, possibly three, mechanisms for regulation of GSK3 are all involved in psychotic illness—the auto-phosphorylation at Y216, the exogenous signal transduction regulated Ser9 site inhibition and, if the association of schizophrenia with the wnt inhibitor DKK4 we reported is true (Proitsi et al., 2008), also via the wnt signaling effects on disruption of the macromolecular complex that brings GSK3 together with β-catenin. On the one hand, this might be taken as positive evidence of a role for GSK3 in psychosis—all of its regulatory mechanisms have been implicated; therefore, the case is stronger. On the other hand, GSK3 lies at the intersection point of very many signaling pathways and so is likely to be implicated in many disorders (as it is), and the fact that in cellular and animal models related to psychosis there is no consistent effect on the enzyme is troublesome.

From a drug discovery perspective, those with GSK3 inhibitors in the pipeline will be watching this space carefully. However, it is worth noting that Mao et al. find very selective effects of DISC1 on GSK3 substrates. Despite convincing evidence of an increase in Y216 phosphorylation, which one would expect to increase activity of GSK3 against all substrates, the authors find no evidence of effects on phosphorylation of the GSK3 substrates Ngn2 or C/EBPα. This is somewhat puzzling and merits further attention, especially as in vitro direct binding of a DISC1 fragment to GSK3 inhibited the action of GSK3 on a range of substrates. Might there be more to the direct interaction of DISC1 with GSK3 than a regulation of Y216 autophosphorylation and activation? If, however, GSK3 regulation turns out to be part of the mechanism of schizophrenia or bipolar disorder, then identifying which of the substrates and which of the many activities of GSK3, including on plasticity and hence cognition (Peineau et al., 2007; Hooper et al., 2007), are important in disease will become the critical task.


Lovestone S, Killick R, Di Forti M, Murray R. Schizophrenia as a GSK-3 dysregulation disorder. Trends Neurosci. 2007 Apr 1 ; 30(4):142-9. Abstract

Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature . 1995 Dec 21-28 ; 378(6559):785-9. Abstract

Jope RS. Lithium and GSK-3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci . 2003 Sep 1 ; 24(9):441-3. Abstract

Proitsi P, Li T, Hamilton G, Di Forti M, Collier D, Killick R, Chen R, Sham P, Murray R, Powell J, Lovestone S. Positional pathway screen of wnt signaling genes in schizophrenia: association with DKK4. Biol Psychiatry . 2008 Jan 1 ; 63(1):13-6. Abstract

Peineau S, Taghibiglou C, Bradley C, Wong TP, Liu L, Lu J, Lo E, Wu D, Saule E, Bouschet T, Matthews P, Isaac JT, Bortolotto ZA, Wang YT, Collingridge GL. LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron . 2007 Mar 1 ; 53(5):703-17. Abstract

Hooper C, Markevich V, Plattner F, Killick R, Schofield E, Engel T, Hernandez F, Anderton B, Rosenblum K, Bliss T, Cooke SF, Avila J, Lucas JJ, Giese KP, Stephenson J, Lovestone S. Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur J Neurosci . 2007 Jan 1 ; 25(1):81-6. Abstract

View all comments by Simon Lovestone

Related News: DISC1: A Matter of Life or Death for Neural Progenitors

Comment by:  Nick Brandon (Disclosure)
Submitted 27 March 2009
Posted 30 March 2009
  I recommend the Primary Papers

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 inhibition of GSK3 by DISC1 in more detail might reveal more novel approaches or encourage more innovative work around this pathway. In addition, I have read the other comment (by Rahman), and though I agree that this work still leaves many questions to be answered, the paper is much more significant and likely reconcilable with previous papers than appreciated. The commentary from Lovestone was very insightful and brings up additional gaps and issues with the present work. Additional experimentation I am sure will tease out more key facets of the DISC1-wnt interaction in the near future.

There are many avenues now to proceed with this work. In particular, from the DISC1-centric view, a GSK3 binding site on DISC1 overlaps with one of the critical core PDE4 binding site. Mao et al. show that residues 211 to 225 are a core part of a GSK3 binding site. Previously, Miles Houslay had shown very elegantly that residues 191-230 form a common binding site (known as common site 1) for both PDE4B and 4D families (Murdoch et al., 2007). It will be important to understand the relationship between GSK3 and PDE4 related signaling in reference to the activity of DISC1 starting at whether a trimolecular complex among DISC1-PDE4-GSK3 can form. Then it will be critical to understand the regulatory interplay among these molecules. For example, it is known that PKA can regulate GSK3 activity (Torii et al., 2008) and the interaction between DISC1 and PDE4, while both GSK3 and PKA can phosphorylate β-catenin (Taurin et al., 2006). The output of these relationships on progenitor proliferation will further deepen insights into the role of DISC1 complexes in neuronal processes. This type of situation is not really surprising for a molecule (DISC1) which has been shown to interact with >100 proteins (Camargo et al., 2007). The context of these interactions in both normal development and disease is likely to be critical to allow understanding of its complete functional repertoire.

Another area where these new findings need to be exploited is in the study of additional animal models. Though the two behavioral endpoint models used in the paper (amphetamine hyperactivity and forced swim test) provide a tantalizing glimpse of the behavioral importance of the complex, it would be critical to look in additional models relevant for schizophrenia and mood disorders. Furthermore, it will be very interesting to look at the effects of GSK3β inhibitors in some of the DISC1 animal models already available and to see if they can reverse all or a subset of reported behaviors. In reviewing a summary of the phenotypes available to date (Shen et al., 2008) there is clearly a number of lines which share the properties with mice injected with DISC1 shRNA into the dentate gyrus and would be of value to look at.

A very exciting paper which I am sure will drive additional research into understanding the role of DISC1 in psychiatry and hopefully encourage drug discovery efforts around this molecular pathway (Wang et al., 2008).


1. 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

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

3. 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

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

5. Torii K, Nishizawa K, Kawasaki A, Yamashita Y, Katada M, Ito M, Nishimoto I, Terashita K, Aiso S, Matsuoka M. Anti-apoptotic action of Wnt5a in dermal fibroblasts is mediated by the PKA signaling pathways. Cell Signal . 2008 Jul 1 ; 20(7):1256-66. Abstract

6. Taurin S, Sandbo N, Qin Y, Browning D, Dulin NO. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J Biol Chem . 2006 Apr 14 ; 281(15):9971-6. Abstract

7. Camargo LM, Collura V, Rain JC, Mizuguchi K, Hermjakob H, Kerrien S, Bonnert TP, Whiting PJ, Brandon NJ. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry . 2007 Jan 1 ; 12(1):74-86. Abstract

8. Shen S, Lang B, Nakamoto C, Zhang F, Pu J, Kuan SL, Chatzi C, He S, Mackie I, Brandon NJ, Marquis KL, Day M, Hurko O, McCaig CD, Riedel G, St Clair D. Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1. J Neurosci . 2008 Oct 22 ; 28(43):10893-904. Abstract

9. Wang Q, Jaaro-Peled H, Sawa A, Brandon NJ. How has DISC1 enabled drug discovery? Mol Cell Neurosci . 2008 Feb 1 ; 37(2):187-95. Abstract

View all comments by Nick Brandon

Related News: DISC1: A Matter of Life or Death for Neural Progenitors

Comment by:  Akira Sawa, SRF Advisor
Submitted 8 April 2009
Posted 8 April 2009

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 preliminary promising answer to this question, which is currently being validated very intensively. These two phenotypes (progenitor cell control and postmitotic migration) may compensate for each other in cortical development; thus, overall cortical pathology looks milder in adults, at least in our preliminary unpublished data using DISC1 knockout mice. We are not sure how this novel function of DISC1 may account for the pathology of Scottish cases. Although I have great respect for the Scottish pioneers of DISC1 study, such as St. Clair, Blackwood, and Muir (I believe that the St. Clair et al., 1990 Lancet paper is one of the best publications in psychiatry), now is the time to pay more and more attention to the question of the molecular pathway(s) involving DISC1 in general schizophrenia (see 2009 SRF roundtable discussion). Unlike the role of APP in Alzheimer’s disease, DISC1 is not a key biological target in general schizophrenia, instead being an entry point to explore much more important targets for schizophrenia. There may be no more need to stick to DISC1 itself in the unique Scottish cases in schizophrenia research. In sum, although there may still be key missing points in this study, I wish to congratulate the authors on their outstanding work.


St Clair D, Blackwood D, Muir W, Carothers A, Walker M, Spowart G, Gosden C, Evans HJ. Association within a family of a balanced autosomal translocation with major mental illness. Lancet . 1990 Jul 7 ; 336(8706):13-6. Abstract

View all comments by Akira Sawa

Related News: DISC1 and SNAP23 Emerge In NMDA Receptor Signaling

Comment by:  Jacqueline Rose
Submitted 2 March 2010
Posted 2 March 2010
  I recommend the Primary Papers

The newly published paper by Katherine Roche and Paul Roche reports SNAP-23 expression in neuron dendrites and examines the possible role of this neuronal SNAP-23 protein. To this point, SNAP-23 has traditionally been discussed in reference to vesicle trafficking in epithelial cells (see Rodriguez-Boulan et al., 2005 for review), so it is of interest to determine the function of SNAP-23 in neurons. Suh et al. report that surface NMDA receptor expression and NMDA-mediated currents are inhibited following SNAP-23 knockdown. Further, SNAP-23 knockdown results in a specific decrease in NR2B subunit insertion; previously, the NR2B subunit has been reported to preferentially localize to recycling endosomes compared to NR2A (Lavezzari et al., 2004). Given these findings, it is reasonable to conclude that SNAP-23 may be involved in maintaining NMDA receptor surface expression possibly by binding to NMDA-specific recycling endosomes.

Interestingly, there is recent evidence that PKC-induced NMDA receptor insertion is mediated by another neuronal SNARE protein; postsynaptic SNAP-25 (Lau et al., 2010). It is possible that activity-induced NMDA receptor trafficking is mediated by SNAP-25, while baseline maintenance of NMDA receptor levels relies on SNAP-23. Other evidence to suggest a strictly regulatory role for SNAP-23 in neuronal NMDA insertion is the finding that activity-dependent receptor insertion from early endosomes has previously been reported to be restricted to AMPA-type glutamate receptors (Park et al., 2004). However, it is possible that activity-induced insertion of AMPA receptors occurs via a distinct endosome pool than NMDA receptors; AMPA and NMDA receptor trafficking has been reported to proceed by distinct vesicle trafficking pathways (Jeyifous et al., 2009).

Although SNAP-23 may not be involved in activity-dependent early endosome receptor trafficking, it is possible that SNAP-23 operates in other pathways linked to activity-induced NMDA receptor trafficking. For instance, SNAP-23 may be the SNARE protein by which lipid raft shuttling of NMDA receptors occurs. SNAP-23 has been found to preferentially associate with lipid rafts over SNAP-25 in PC12 cells (Salaün et al., 2005). As well, NMDA receptors have been found to associate with lipid raft associated proteins flotilin-1 and -2 in neurons (Swanwick et al., 2009). Lipid raft trafficking of NMDA receptors to post-synaptic densities has been reported to follow global ischemia (Besshoh et al., 2005), and the possibility remains that under certain circumstances, NMDA trafficking occurs by lipid raft association to SNAP-23.

Taken together, the discovery of post-synaptic SNARE proteins offers several avenues of research to determine their roles and functions in glutamatergic synapse organization. Further, investigating disruption of synaptic receptor organization presents several possibilities for potential etiologies of disorders linked to compromised glutamate signaling like schizophrenia.


Besshoh, S., Bawa, D., Teves, L., Wallace, M.C. and Gurd, J.W. (2005). Increased phosphorylation and redistribution of NMDA receptors between synaptic lipid rafts and post-synaptic densities following transient global ischemia in the rat brain. Journal of Neurochemistry, 93: 186-194. Abstract

Jeyifous, O., Waites, C.L., Specht, C.G., Fujisawa, S., Schubert, M., Lin, E.I., Marshall, J., Aoki, C., de Silva, T., Montgomery, J.M., Garner, C.C. and Green, W.N. (2009). SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway. Nature Neuroscience, 12: 1011-1019. Abstract

Lau, C.G., Takayasu, Y., Rodenas-Ruano, A., Paternain, A.V., Lerma, J., Bennet, M.V.L. and Zukin, R.S. (2010). SNAP-25 is a target of protein kinase C phosphorylation critical to NMDA receptor trafficking. Journal of Neuroscience, 30: 242-254. Abstract

Lavezzari, G., McCallum, J., Dewey, C.M. and Roche, K.W. (2004). Subunit-specific regulation of NMDA receptor endocytosis. Journal of Neuroscience, 24: 6383-6391. Abstract

Park, M., Penick, E.C., Edward, J.G., Kauer, J.A. and Ehlers, M.D. (2004). Recycling endosomes supply AMPA receptors for LTP. Science, 305: 1972-1975. Abstract

Rodriguez-Boulan, E., Kreitzer, G. and Müsch, A. (2005) Organization of vesicular trafficking in epithelia. Nature Reviews: Molecular Cell Biology, 6: 233-247. Abstract

Salaün, C., Gould, G.W. and Chamberlain, L.H. (2005). The SNARE proteins SNAP-25 and SNAP-23 display different affinities for lipid rafts in PC12 cells. Journal of Biological Chemistry, 280: 1236-1240. Abstract

Suh, Y.H., Terashima, A., Petralia, R.S., Wenthold, R.J., Isaac, J.T.R., Roche, K.W. and Roche, P.A. (2010). A neuronal role for SNAP-23 in postsynaptic glutamate receptor trafficking. Nat Neurosci. 2010 Mar;13(3):338-43. Abstract

Swanwick, C.C., Shapiro, M.E., Chang, Y.Z. and Wenthold, R.J. (2009). NMDA receptors interact with flotillin-1 and -2, lipid raft-associated proteins. FEBS Letters, 583: 1226-1230. Abstract

View all comments by Jacqueline Rose