NYAS Symposium Surveys DISC1 Role in Schizophrenia

15 July 2008. Last May, the New York Academy of Sciences (NYAS), together with the American Chemical Society's New York Section, hosted a one-day symposium entitled “DISC1 and the Neurodevelopmental Hypothesis of Schizophrenia.” The meeting, sponsored by the NYAS Biochemical Pharmacology Discussion Group, was hosted by Julia Heinrich, formerly with Wyeth Discovery Neuroscience and Robin Kleiman from Pfizer, Inc. The organizers invited four experts to present their ideas on how disrupted in schizophrenia (DISC1) and its partners relate to the etiology of the disease and to discuss potential therapeutic approaches that might be suggested by the latest data. The full symposium is currently available via webcast for NYAS members and SRF readers (Contact us for details). Here we present some of the major points of the presentations.

Heinrich started the meeting with an overview of schizophrenia, including a brief history of the research linking the disease with DISC1. There are many hypotheses on the causes of schizophrenia, including those that point to neurochemical imbalances, epigenetic factors, and neurodevelopmental problems. One of the major questions facing the field, suggested Heinrich, is how early the latter might occur ahead of the overt phenotype. There are indications, such as obstetric complications, reduced brain volume in infants, and childhood cognitive deficits, which all occur early, that schizophrenia could be grounded in early developmental events. The more recent identification of candidate susceptibility genes, including DISC1, that play a role in development, strengthens that argument.

Continuing on that theme, Akira Sawa, from Johns Hopkins University, Baltimore, Maryland, noted that there is a distinction being made in the field between pathogenesis and pathophysiology of schizophrenia (see review by Lewis et al., 2005). While pathophysiology may be concurrent with the phenotype, pathogenesis may occur much earlier. Susceptibility genes have, and will be, helpful in studying the pathogenesis, Sawa said, particularly the genes neuregulin-1, dysbindin, and DISC1.

DISC1 was discovered when University of Edinburgh researchers identified a chromosomal translocation in a large Scottish family with mental disorders (see St. Clair et al., 1990). That translocation was subsequently shown to break the DISC1 gene (see Millar et al., 2000). Researchers later showed that DISC1 associates with schizophrenia in other populations as well (see Hodgkinson et al., 2004 and Hamshere et al., 2005). Work from Tyrone Canon’s lab at UCLA then showed that DISC1 is important for gray matter morphology (see Cannon et al., 2005), suggesting variations in the gene may have an impact on brain formation or brain malformation. Together, these papers represent seminal contributions to the study of DISC1 in schizophrenia, suggested Sawa.

Sawa reviewed what is known about the biology of DISC1. The protein exists in many different isoforms, maybe even as many as 40-50, said Sawa, and it has several subcellular locations and multiple, context-dependent functions. It is found in the post-synaptic density, for example, where it binds to post-synaptic markers such as PSD95; it is also found at the centrosome, the organizing center for microtubules; and it associates with the nucleus and mitochondria. From the schizophrenia perspective, the centrosome and post-synaptic density locations may be the most important, said Sawa. He suggested that it is also possible that the gene is duplicated elsewhere in the genome. If true, that will make DISC1 knockout models even more difficult to achieve, said Sawa.

Currently there are five mouse models of abnormal DISC1, but none is a complete knockout because it is very difficult to deplete all isoforms of the protein, said Sawa. For this reason, knockdown models using RNAi have been useful, showing that the protein is important for corticogenesis, for example. But its role appears context-dependent. In the cortex, suppressing DISC1 (at least some isoforms) delays cell migration, whereas in the adult dentate gyrus it accelerates it, suggesting DISC1 plays a role in adult neurogenesis (see SRF related news story).

DISC1 is found on centrosomes in developing neurons and the post-synaptic density in mature neurons, suggesting that DISC1 variation could increase the risk for schizophrenia in two ways early during development, and later by interfering with neuronal circuitry. Sawa focused mostly on the centrosomal role.

The centrosome is the organizing center for the microtubules, which are essential for cell division, polarization, migration, and neuronal differentiation. The microtubules are critical for neurodevelopment. Sawa’s group has found that DISC1 is part of a large dynein protein complex at the centrosome, and that without DISC1, microtubule formation is compromised (see Kamiya et al., 2005). DISC1 appears to be necessary to maintain the dynein complex at the centrosome.

Genetic variations in other centrosomal proteins have also been linked to neuropsychiatric disorders. Pericentriolar material 1 (PCM1), for example, has been linked to schizophrenia (see SRF related news story), which strengthens the idea that centrosomal actions of DISC1 may be germane to the disorder, and a disease-causing protein encoded by the (BBS4) gene, linked to Bardet-Biedl syndrome, a disease with neuropsychiatric symptoms binds to PCM1 (see Kim et al., 2004). Now, in a paper in press in the Archives of General Psychiatry, Sawa and colleagues will show link of DISC1, PCM1, and BBS proteins in the pathology of schizophrenia via both genetic and biological approaches. Some of this work was already presented at the 2006 Society for Neuroscience meeting in Atlanta, Georgia (see SRF related news story). DISC1 also binds to other centrosomal proteins, such as NDE1 and NDEL1 (also known as NUDE and NUDEL, respectively) (see SRF related news story). In collaboration with Anil Malhotra’s group at Zucker Hillside Hospital, Glen Oaks, New York, Sawa and colleagues recently showed, using genetic and biological evidence, that DISC1, NDE1, and NDEL1 are linked with each other in the pathology of schizophrenia (see Burdick et al., 2008).

Nick Brandon outlined some of the ongoing DISC1 work at Wyeth Neuroscience Research, Princeton, New Jersey. Industry is interested in DISC1 because it may be useful for identifying “druggable” target molecules and because it might provide some useful animal models, suggested Brandon. On the former, Brandon and colleagues have carried out extensive yeast two-hybrid screens and mass-spec analysis of DISC1 complex to identify DISC1 partners, finding over 400 different protein molecules (see Camargo et al., 2007). From this work several protein networks that may be pertinent to schizophrenia were found, including those containing the cysteine protease NDEL1 and the cyclic AMP degrading enzyme phosphodiesterase 4 (PDE4). Analysis of the interactome also showed that it was enriched in proteins that are involved in synaptic activity and glutamate receptor function. The proteins are involved in almost every aspect of synapse biology from formation to stabilization. These networks provide a template for others in the field to build from, suggested Brandon.

Brandon said that all the indications from this work are that DISC1 is a synaptic protein. What its role is at the synapse, and how it is regulated, are key questions. Brandon and colleagues have begun to address these, and he treated the audience to some snippets of work in progress. Using highly specific antibodies that recognize different exons of mouse Disc1, the researchers have mapped expression of the protein in primary hippocampal neurons. The protein appears to be perinuclear early on, but after 14 days in vitro Disc1 is expressed widely in the neuron, including at dendritic sites, where it colocalizes with PSD95, a synaptic marker. Biochemical analysis also strongly suggests a synaptic localization for Disc1—the protein is enriched in synaptosomes and isolated PSD fractions. Brandon and colleagues are now working on identifying exactly which isoforms are present in these fractions. Preliminary analysis suggests that the isoform distribution may be quite complex, and more antibodies are needed to get a better picture of the synaptic isoforms, said Brandon. Figuring out which isoforms are present and identifying their binding partners are crucial steps to deciphering the synaptic role of DISC1.

One well-known DISC1 binding partner is NDEL1, which also binds LIS1, a protein linked to lissencephaly (see SRF related news story). As Sawa mentioned, both DISC1 and NDEL1 are found at the centrosome, as is LIS1. Brandon discussed some of the properties of NDEL1, which is still not well understood. The protein regulates the assembly of neurofilaments (Nguyen et al., 2004) and together with another protein, vimentin, is crucial for neurite outgrowth (Shim et al., 2008). It also plays important roles in cell migration (Shen et al., 2008) and neurogenesis (Shu et al., 2004). Some of these functions are probably dependent on DISC1, since it acts as a cargo receptor for NDEL1 complexes in axons (see SRF related news story). Brandon showed that DISC1 and NDEL1 are co-expressed in the hippocampus, but not necessarily in other regions of the brain—for example, the hypothalamus—indicating the interaction between the two proteins is context dependent. His group found that NDEL1 also binds to a distinct domain on DISC1 at the C-terminus (see Brandon et al., 2004) via a Ndel1 domain that includes amino acids leucine 266 and glutamate 267—when those residues are mutated, the binding to DISC1 is lost. Those amino acids are also required for neurite outgrowth, suggesting that DISC1 plays a role in that NDEL1 regulated process.

Interestingly, NDEL1 was independently identified as an endoligopeptidase that cleaves small neuropeptides, and cysteine 273 is essential for this activity. Given it binds NDEL1 very close to this cysteine residue, could DISC1 somehow regulate NDEL1 activity? Assays with purified proteins show that DISC1 is, in fact, a competitive inhibitor of NDEL1 peptidase activity (see Hayashi et al., 2005), but it was not clear if this had any physiological significance, said Brandon. To address this, in collaboration with a research group at the University of Sao Paolo in Brazil led by Mirian Hayashi, Sawa’s group developed a cell-based test of NDEL1 activity. In a paper that is in preparation, they show that NDEL1 enzymatic activity increases as PC12 cells grow in culture and that loss of cysteine 273 reduces neurite outgrowth. The groups next plan to study the relationship between peptidase activity and neurite growth in hippocampal cells. They also plan to identify which substrates are key to the function of Ndel1 in neurite outgrowth.

How do DISC1 variations relate to the pathophysiology and phenotypes seen in schizophrenia? Katherine Burdick, North Shore Long Island Jewish Health System, reviewed some of the clinical research on DISC1, and it fits with known schizophrenia endophenotypes and DISC1 molecular interactions.

Burdick reminded the audience that the impact of DISC1 variants, and in fact most genetic risk for schizophrenia, is likely to be small and transmitted in a polygenic, non-Mendelian fashion. Genetic variability alone cannot account for the disease, and there are numerous environmental influences that have been linked to schizophrenia, many associated with the critical peri- and postnatal period of development. Together, the genetic and epidemiological data suggest that schizophrenia may have a neurodevelopmental etiology.

Genetic variations in DISC1 have been linked to various psychiatric disorders, including bipolar and schizoaffective disorders, major depression, and more recently, autism. These linkages suggest that DISC1 may impact some traits that overlap among all these disorders. Increased risk for some positive symptoms of schizophrenia, such as delusions and hallucinations, have been linked to specific single nucleotide polymorphisms (SNPs) and haplotypes of the DISC1 gene (Hennah et al., 2003), and also with various cognitive domains, such as verbal and spatial working memory, subserved by hippocampal and prefrontal cortex function (see Burdick et al., 2005), but the data are quite complex, said Burdick. Different markers within the gene have been associated with cognitive deficits in different studies. This may reflect methodological differences among studies, but it could also be indicative that there are different loci within the gene that impact cognition, she said.

How do these functional affects of DISC1 variants relate to its structural effects on the brain? Burdick reviewed some of the evidence linking DISC1 to brain abnormalities. Phil Szeszko, her colleague in Anil Malhotra's group, has found that one polymorphism, a leucine to phenylalanine mutation at position 607, is linked to reduced gray matter in the anterior cingulate and superior frontal gyrus (Szeszko et al., 2007), suggesting decreased gray matter in prefrontal cortex, one area of the brain that has been consistently associated with the disease. Other groups have also found reduced hippocampal volume in leu607phe carriers and also learning and memory effects (see Cannon et al., 2005). Another single nucleotide polymorphism (SNP), at position 704 (serine/cysteine), has also been linked to reduced hippocampal volume (ser704 homozygotes) and abnormal hippocampal activation in working memory and episodic memory tests. These findings tie together cognitive effects of DISC1 variation with structural consequences, suggested Burdick.

Since schizophrenia is likely polygenic, how do genetic variations in DISC1 relate to other genetic variations, particularly in genes that interact with DISC1, such as NDEL1? Burdick and colleagues found that there are four SNPs in the NDEL1 gene that form a block that is in linkage disequilibrium with schizophrenia. Two common haplotypes form this block. The less common is associated with the disease and increases risk by about 1.3-fold. A tagging SNP in the same location also increases risk by 1.5-fold, but when viewed in the context of DISC1 genetic variation, a slightly different picture emerges. The tagging SNP risk allele (G) only confers risk (2.5-fold) in DISC1 ser704 homozygotes, suggesting there is epistasis at work. Interestingly, the DISC1 serine at position 704 is in close proximity to the Ndel1 binding site.

Other groups have found that there are similar genetic interactions between DISC1 and the NDEL1 homolog NDE1 (see SRF related news story). Burdick and colleagues have looked at NDEL1-DISC1 genetic interactions and found that they are opposite to that for NDEL1 and DISC1. While the serine at DISC1 704 is required for the NDEL1 variant to have any effect, cysteine is needed at position 704 in the case of NDEL. This is consistent with biochemical data showing that NDEL1 binds to the cys704 DISC1 preferentially, while NDE1 binds best to the ser704 DISC1 (see also Burdick et al., 2008).

How do these observations tie in with the neurodevelopmental hypothesis of schizophrenia? Burdick suggested that given DISC1’s multiple roles in embryonic development and near the age of puberty, and its role in adult neurogenesis (see SRF related news story), it is poised to be a central player in pathogenesis. “Perturbation of NDEL1/NDE1 balance might result in abnormal binding of these proteins to DISC1, disrupting the coordinated functions of the DISC1-associated protein complex to interfere with normal neuron growth and migration,” said Burdick.

The structural and functional consequences of DISC1 variation in humans is also consistent with changes seen in mice with mutations in the gene. Steven Clapcote, University of Edinburgh, Scotland, reviewed some of the data that have emerged for mouse models of schizophrenia based on DISC1 mutagenesis. In collaboration with colleagues at RIKEN Genomic Science Center, Yokohama, Japan, Clapcote and colleagues have made DISC1 mutant mice using a random mutagenesis approach. This has resulted in mice strains with five different mutations in the Disc1 gene, three in the largest exon (No. 2) and two in exon 11. Clapcote said that one of the exon 11 mutations (H738N) might interfere with Disc1 binding to Grb2, an adaptor molecule that links receptor tyrosine kinases in the ERK signal transduction pathway (see Shinoda et al., 2007), but this mutation has not been fully characterized yet. Two of the mutations in exon 2, Q31L and L100P, have been characterized, and Clapcote reviewed some of the properties of the mice.

SRF has substantially covered this work (see SRF related news story). Briefly, the two mutations have somewhat different effects in mice. Mice with the L100P mutation have slightly reduced brain volume—especially in the cortex and cerebellum. The latter was a bit surprising, said Clapcote. His group is currently following that up to get a better understanding of the relationship between Disc1 and brain size.

Behaviorally, both mutations have significant, though not always similar, effects. Both mutant lines showed reduced prepulse inhibition, latent inhibition, and impaired spatial working memory. But in an open field test (a model of psychomotor agitation—one of the positive symptoms of schizophrenia), only the L100P mice are hyperactive. This hyperactivity was exacerbated by amphetamines—psychostimulants to which schizophrenia patients are particularly sensitive. The Q31L mice, on the other hand, showed both reduced social interaction and reduced interest in sucrose solutions—a sign of anhedonia. In a forced swim test, the Q31L animals also give up and float more readily—a sign of depression.

The two strains also differ in their response to antidepressants. Rolipram, a phosphodiesterase 4B (PDE4B) inhibitor, rescued prepulse inhibition in the L100P animals but not in the Q31L mice. In the latter strain, rolipram also had no effect on depression as judged by performance in the forced swim test, but the antidepressant bupropion did work. The differential effects of the drugs may be related to Disc1 binding to Pde4b The two must dissociate for the phosphodiesterase to become active, and Clapcote noted that the Q31L animals had about half as much Pde4b activity as wild-type, which might explain their resistance to rolipram. “If PDE activity is already low, the dose may not be sufficient to reduce it any further,” he suggested. But interestingly, despite lower Pde4b activity, the Q31L mice are more depressed—not less. Though more work is needed to sort out the relationships between these mutations, their different phenotypes, and Disc1 function, their differential response to drugs might be a pharmacogenomic model for the different types of responses reported in patients with different genotypes, suggested Clapcote.—Tom Fagan.

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).

View all comments by Anil Malhotra

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Angus Nairn
Submitted 29 December 2005
Posted 31 December 2005
  I recommend the Primary Papers

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

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Patricia Estani
Submitted 2 January 2006
Posted 2 January 2006
  I recommend the Primary Papers

Related News: PCM1 Gene Is Linked to Altered Brain Morphology in Schizophrenia

Comment by:  Akira Sawa, SRF Advisor
Submitted 22 August 2006
Posted 22 August 2006

Many linkage analyses have reproducibly reported 8p21-22 as a linkage hot locus for schizophrenia. The gene coding for neuregulin-1 is regarded as a factor that contributes to the linkage peak, but other genes may also be involved. Dr. Gurling and colleagues have conducted an excellent association study and obtained evidence that the gene coding for pericentriolar material 1 (PCM1) is associated with schizophrenia.

The results from the genetic portions of this are consistent with our unpublished biological study. (The abstract of Kamiya et al. has been submitted to SFN meeting at Atlanta in October 2006.) In exploring protein interactors of disrupted-in-schizophrenia-1 (DISC1), a promising risk factor for schizophrenia and bipolar disorder, we already came across PCM1 as a potential protein interactor of DISC1. This interaction has been confirmed by yeast two-hybrid and biochemical methods. In immunofluorescent cell staining, a pool of DISC1 and PCM1 are co-stained at the centrosome. Therefore, this genetic study is really encouraging us to move beyond our preliminary study on DISC1 and PCM1.

Of interest, Gurling and colleagues reported in the paper that the cases with the PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex. This may be in accordance with our previous publication (Sawamura et al., 2005) reporting the alteration in subcellular distribution of DISC1 in the orbitofrontal cortex of the patients with schizophrenia.

Although a possible link of DISC1 and PCM1 in the pathophysiology of schizophrenia is still hypothetical, the intriguing work by Dr. Gurling and colleagues may now open a window in studying the centrosomal “pathway” in association with schizophrenia. Epistatic interactions on DISC1, PCM1, and related molecules may also be of interest for future studies.

View all comments by Akira Sawa

Related News: PCM1 Gene Is Linked to Altered Brain Morphology in Schizophrenia

Comment by:  Mary Reid
Submitted 20 August 2006
Posted 23 August 2006

Regarding the possibility that PCM1 may have ties to DISC1, it's of interest that when PCM1 function is inhibited there is reduced targeting of centrin, pericentrin and ninein to the centrosome (1). Miyoshi and colleagues (2) report that their data indicate that DISC1 localizes to the centrosome by binding to kendrin/pericentrinB. Might there be a failure of DISC1 to localize in the centrosome in PCM1 deficiency?

Do these families with PCM1-associated schizophrenia also have a history of scleroderma? It is also of interest that PCM1 is an autoantigen target in scleroderma (3), and there is a report of cerebral involvement of scleroderma presenting as schizophrenia-like psychosis (4).

Abelson Helper Integration Site 1 (AHI1) gene is a candidate gene for schizophrenia and mutations in AHI1 underlie the autosomal recessive Joubert Syndrome in which cerebellar vermis hypoplasia is reported.(5) Increased cerebellar vermis white-matter volume has recently been reported in males with schizophrenia.(6)

It's interesting that mutations in the centrosomal protein nephrocystin-6 may also cause Joubert syndrome and that it activates ATF4. (7) Morris and colleagues (8) find that DISC1 interacts with ATF4 - a schizophrenia locus on 22q13 and ATF5. Perhaps failure of DISC1 to localize to the centrosome due to PCMI deficiency may also result in reduced activation of ATF4/5.

In view of the study by Al Sarraj and colleagues (9) finding that ATF4/5 stimulate asparagine synthetase activity might we suspect that reduced activation of ATF4 and ATF5 in schizophrenia may explain the decreased CSF asparagine levels reported (10) Perhaps asparagine synthetase might be a suitable drug target in schizophrenia. Of further relevance is the processed pseudogene for asparagine synthetase found upstream of GNAL -18p11, a region linked to bipolar disorder and schizophrenia. (11) Hirotsune and colleagues (12) report that an expressed pseudogene regulates messenger-RNA stability of its homologous coding gene.

Might we also suspect a role for DISC1 in oligodendrocyte dysfunction in schizophrenia? Reduced myelination is reported in neonatal rats deprived of asparagine?(13) It would seem relevant however that Mason and colleagues (14) find that ATF5 regulates proliferation and differentiation of oligodendrocytes, with loss of function resulting in accelerated oligodendrocyte differentiation

References:

1. Dammermann A, Merdes A. Assembly of centrosomal proteins and microtubule organization depends on PCM-1. J Cell Biol. 2002 Oct 28;159(2):255-66. Epub 2002 Oct 28. Abstract

2. Miyoshi K, Asanuma M, Miyazaki I, Diaz-Corrales FJ, Katayama T, Tohyama M, Ogawa N. DISC1 localizes to the centrosome by binding to kendrin. Biochem Biophys Res Commun. 2004 May 14;317(4):1195-9. Abstract

3. Bao L, Zimmer WE, Balczon R. Autoepitope mapping of the centrosome autoantigen PCM-1 using scleroderma sera with anticentrosome autoantibodies. Autoimmunity. 1995;22(4):219-28. Abstract

4. Muller N, Gizycki-Nienhaus B, Botschev C, Meurer M. Cerebral involvement of scleroderma presenting as schizophrenia-like psychosis. Schizophr Res. 1993 Aug;10(2):179-81. Abstract (5) Eur J Hum Genet. 2006 Jun 14; [Epub ahead of print] AHI1, a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to schizophrenia. Amann-Zalcenstein D, Avidan N, Kanyas K, Ebstein RP, Kohn Y, Hamdan A, Ben-Asher E, Karni O, Mujaheed M, Segman RH, Maier W, Macciardi F, Beckmann JS, Lancet D, Lerer B. (6) J Psychiatr Res. 2006 Apr 18; [Epub ahead of print] Increased cerebellar vermis white-matter volume in men with schizophrenia. Lee KH, Farrow TF, Parks RW, Newton LD, Mir NU, Egleston PN, Brown WH, Wilkinson ID, Woodruff PW (7) Nat Genet. 2006 Jun;38(6):674-81. Epub 2006 May 7. The centrosomal protein nephrocystin-6 is mutated in Joubert syndrome and activates transcription factor ATF4. Sayer JA, Otto EA, O'Toole JF, Nurnberg G, Kennedy MA, Becker C, Hennies HC, Helou J, Attanasio M, Fausett BV, Utsch B, Khanna H, Liu Y, Drummond I, Kawakami I, Kusakabe T, Tsuda M, Ma L, Lee H, Larson RG, Allen SJ, Wilkinson CJ, Nigg EA,Shou C, Lillo C, Williams DS, Hoppe B, Kemper MJ, Neuhaus T, Parisi MA, Glass IA, Petry M, Kispert A, Gloy J, Ganner A, Walz G, Zhu X, Goldman D, Nurnberg P, Swaroop A, Leroux MR, Hildebrandt F. (8) Hum Mol Genet. 2003 Jul 1;12(13):1591-608. Links DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Morris JA, Kandpal G, Ma L, Austin CP. (9) Biol Chem. 2005 Sep;386(9):873-9. Links Regulation of asparagine synthetase gene transcription by the basic region leucine zipper transcription factors ATF5 and CHOP. Al Sarraj J, Vinson C, Thiel G. (10) Nippon Rinsho. 1992 Jul;50(7):1643-9. Links [Amino acid metabolism in endogenous psychoses: significance of amino acids as neurotransmitter, precursor of monoamines and allosteric regulator of neuro-receptors] Doi N. (11) Mol Psychiatry. 2000 Sep;5(5):495-501. Links Sequence and genomic organization of the human G-protein Golfalpha gene (GNAL) on chromosome 18p11, a susceptibility region for bipolar disorder and schizophrenia. Vuoristo JT, Berrettini WH, Overhauser J, Prockop DJ, Ferraro TN, Ala-Kokko L. (12) Nature. 2003 May 1;423(6935):26-8. An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene. Hirotsune S, Yoshida N, Chen A, Garrett L, Sugiyama F, Takahashi S, Yagami K, Wynshaw-Boris A, Yoshiki A. (13) Dev Neurosci. 1982;5(4):332-44. Brain development in neonatal rats nursing asparagine-deprived dams. Newburg DS, Fillios LC. (14) Mol Cell Neurosci. 2005 Jul;29(3):372-80. ATF5 regulates the proliferation and differentiation of oligodendrocytes. Mason JL, Angelastro JM, Ignatova TN, Kukekov VG, Lin G, reene LA, Goldman JE.

View all comments by Mary Reid

Related News: PCM1 Gene Is Linked to Altered Brain Morphology in Schizophrenia

Comment by:  Mary Reid
Submitted 10 September 2006
Posted 12 September 2006

Den Hollander and colleagues (1) report that mutations in CEP290-nephrocystin-6 are a frequent cause of Leber's Congenital Amaurosis (LCA). Autistic signs are reported in both Joubert syndrome and LCA (2,3). Perhaps asparagine may be useful for those with LCA and dysmyelination.

References:

1. den Hollander AI, Koenekoop RK, Yzer S, Lopez I, Arends ML, Voesenek KE, Zonneveld MN, Strom TM, Meitinger T, Brunner HG, Hoyng CB, van den Born LI, Rohrschneider K, Cremers FP. Mutations in the CEP290 (NPHP6) Gene Are a Frequent Cause of Leber Congenital Amaurosis. Am J Hum Genet. 2006 Sep;79(3):556-61. Epub 2006 Jul 11. Abstract

2. Curless RG, Flynn JT, Olsen KR, Post MJ. Leber congenital amaurosis in siblings with diffuse dysmyelination. Pediatr Neurol. 1991 May-Jun;7(3):223-5. Abstract

3. Rogers SJ, Newhart-Larson S. Characteristics of infantile autism in five children with Leber's congenital amaurosis. Dev Med Child Neurol. 1989 Oct;31(5):598-608. Abstract

View all comments by Mary Reid

Related News: PCM1 Gene Is Linked to Altered Brain Morphology in Schizophrenia

Comment by:  Mary Reid
Submitted 25 September 2006
Posted 28 September 2006

The asparagine synthetase gene has been mapped to 7q21.3 (1). Childhood-onset schizophrenia/autistic disorder has been described in a child with a translocation breakpoint at 7q21. Of further interest is that alcohol/drug abuse, severe impulsivity, paranoid personality, and language delay have been reported in other family members carrying this translocation.

Maybe the increased risk of schizophrenia following famine may be explained by the fact that starvation induces expression of ATF4 and asparagine synthetase. Is there an increased risk of mutation in these genes as a long-term response to famine?

References:

1. Heng HH, Shi XM, Scherer SW, Andrulis IL, Tsui LC. Refined localization of the asparagine synthetase gene (ASNS) to chromosome 7, region q21.3, and characterization of the somatic cell hybrid line 4AF/106/KO15. Cytogenet Cell Genet. 1994;66(2):135-8. Abstract

2. Yan WL, Guan XY, Green ED, Nicolson R, Yap TK, Zhang J, Jacobsen LK, Krasnewich DM, Kumra S, Lenane MC, Gochman P, Damschroder-Williams PJ, Esterling LE, Long RT, Martin BM, Sidransky E, Rapoport JL, Ginns EI. Childhood-onset schizophrenia/autistic disorder and t(1;7) reciprocal translocation: identification of a BAC contig spanning the translocation breakpoint at 7q21. Am J Med Genet. 2000 Dec 4;96(6):749-53. Abstract

View all comments by Mary Reid

Related News: SfN Atlanta: Baby Steps in the Study of DISC1

Comment by:  Hakon Heimer
Submitted 13 November 2006
Posted 14 November 2006

In response to our query (see above), Weidong Li sends the following update:

In our poster at the Neuroscience 2006 meeting, I reported on my work in Alcino Silva and Tyrone Cannon's labs at UCLA, using an inducible system to study the effect of mutant DISC1 on behavior. We demonstrated that induction of the mutant protein at postnatal day 7 resulted in impaired spatial working memory, reduced social preference, increased depressive behavior, reduced dendritic complexity, and reduced basal synaptic activity in hippocampal neurons at adulthood.—Weidong Li

View all comments by Hakon Heimer

Related News: Messing with DISC1 Protein Disturbs Development, and More

Comment by:  Ali Mohammad Foroughmand
Submitted 16 December 2006
Posted 16 December 2006
  I recommend the Primary Papers

Related News: DISC1 Delivers—Genetic, Molecular Studies Link Protein to Axonal Transport

Comment by:  Akira Sawa, SRF Advisor
Submitted 12 January 2007
Posted 12 January 2007

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.

View all comments by Akira Sawa

Related News: DISC1 Delivers—Genetic, Molecular Studies Link Protein to Axonal Transport

Comment by:  Luiz Miguel Camargo (Disclosure)
Submitted 13 January 2007
Posted 13 January 2007

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.).

View all comments by Luiz Miguel Camargo

Related News: New Spin on DISC1—Mouse Mutation Impairs Behavior

Comment by:  Akira Sawa, SRF Advisor
Submitted 8 May 2007
Posted 8 May 2007

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.

View all comments by Akira Sawa

Related News: New Spin on DISC1—Mouse Mutation Impairs Behavior

Comment by:  Christopher Ross
Submitted 8 May 2007
Posted 8 May 2007

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.

View all comments by Christopher Ross

Related News: New Spin on DISC1—Mouse Mutation Impairs Behavior

Comment by:  Nick Brandon (Disclosure)
Submitted 8 May 2007
Posted 8 May 2007

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.

View all comments by Nick Brandon

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.

References:

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.

References:

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: Learning from Drug Candidates—New Kid Targets Same Block

Comment by:  Dan Javitt, SRF Advisor
Submitted 10 November 2008
Posted 10 November 2008

The article by Homayoun and Moghaddam is another in an excellent series of articles investigating effects of metabotropic agents on brain function relevant to schizophrenia. As opposed to previous studies by this group that targeted rodent medial prefrontal cortex, which is used as a model of dorsolateral prefrontal cortex in humans, this study targets orbitofrontal cortex. The main finding of this study, like prior studies by this group, is that effects of the NMDA antagonist MK-801 can be reversed by the LY354740, a selective metabotropic group 2/3 agonist. LY354740 has previously been shown to reverse ketamine effects in humans (Krystal et al., 2005) and to be effective in treatment of generalized anxiety disorder in humans (Dunayevich et al., 2008). It is pharmacologically related to LY2130023 (Rorick-Kehn et al., 2007), a compound that has shown efficacy in treatment of schizophrenia (Patil et al., 2007).

In addition, the study builds upon prior studies of mGluR5 agonists (e.g., Darrah et al., 2008) to show that CDPPB, a novel modulator of mGluR5 receptors, also reverses acute effects of MK-801. mGluR5 receptors interact closely with NMDA receptors. It has been known for a long time that mGluR5 antagonists induce symptoms similar to those of NMDA antagonists, suggesting a potential role for agents that can stimulate mGluR5 activity. However, mGluR5 receptors are prone to downregulation following application of agonists, so the evaluation of mGluR5 receptors as a therapeutic target in schizophrenia has had to await development of high-affinity, CNS penetrant mGluR5 modulators that do not cause desensitization. The similar effects of an mGluR2/3 agonist and an mGluR5 modulator suggest that multiple approaches may be taken to normalize NMDA function in schizophrenia, including modulation of both presynaptic glutamate and postsynaptic NMDA function. mGluR5 receptors are active also in visual cortex (Sarihi et al., 2008), and so would potentially reverse effects of NMDA antagonists on sensory, as well as frontal deficits associated with schizophrenia.

In our own research studies, we have found that structural white matter alterations in orbitofrontal cortex correlate with ability to identify emotion (Leitman et al., 2007), attesting to the importance of this brain region to cognitive dysfunction in schizophrenia. Structural change in this region also correlates with aggression (Hoptman et al., 2005), which is an important issue determining clinical outcome in individuals with schizophrenia. Our findings thus support the concept that glutamatergic neurotransmission within orbitofrontal cortex may play as important a role in schizophrenia as dysfunction within dorsolateral prefrontal cortex, and deserves to be studied with equal fervor.

Despite the tremendous value of the study, every silver lining must have its cloud. In this case, the caveat relates to the finding that effects of MK-801 in this model were also reversed by haloperidol and clozapine. On the one hand, it is good news, as it suggests that metabotropic compounds may be as effective as antipsychotics in treating the well-known dopaminergic dysregulation associated with schizophrenia. In the one published clinical trial of LY2130023 (Patil et al., 2007), the compound proved almost as effective as olanzapine despite use of what may not have been an optimized dose.

On the other hand, however, it suggests that the orbitofrontal model, like the prior dorsolateral model, does not yet capture the aspects of schizophrenia that respond poorly to antipsychotics, such as primary negative symptoms and cognitive dysfunction. It is important to develop compounds that are as good as antipsychotics in treating positive symptoms, but without the well-known side metabolic and motor side effects. However, it is even more important to develop treatments that target aspects of schizophrenia that remain unresponsive to current therapeutic approaches. To date, no clinical data are available regarding effects of either mGlu2/3 agonists or mGlu5 modulators on neurocognition in humans. The ultimate challenge may be to show that metabotropic modulators can reverse effects of NMDA antagonists in models where antipsychotics such as haloperidol or clozapine prove ineffective. Another critical issue is whether these compounds will be effective during longer-term treatment (Imre et al., 2006). To do so, longer-term treatment studies are required. Nevertheless, these data provide further hope to the development of non-dopaminergic treatment approaches in schizophrenia.

References:

Darrah JM, Stefani MR, Moghaddam B. Interaction of N-methyl-D-aspartate and group 5 metabotropic glutamate receptors on behavioral flexibility using a novel operant set-shift paradigm. Behav Pharmacol. 2008 May 1;19(3):225-34. Abstract

Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, Tollefson GD. Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology. 2008 Jun 1;33(7):1603-10. Abstract

Hoptman MJ, Volavka J, Weiss EM, Czobor P, Szeszko PR, Gerig G, Chakos M, Blocher J, Citrome LL, Lindenmayer JP, Sheitman B, Lieberman JA, Bilder RM. Quantitative MRI measures of orbitofrontal cortex in patients with chronic schizophrenia or schizoaffective disorder. Psychiatry Res. 2005 Nov 30;140(2):133-45. Abstract

Imre G, Fokkema DS, Ter Horst GJ. Subchronic administration of LY354740 does not modify ketamine-evoked behavior and neuronal activity in rats. Eur J Pharmacol. 2006 Aug 21;544(1-3):77-81. Abstract

Krystal JH, Abi-Saab W, Perry E, D'Souza DC, Liu N, Gueorguieva R, McDougall L, Hunsberger T, Belger A, Levine L, Breier A. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology (Berl). 2005 Apr 1;179(1):303-9. Abstract

Leitman DI, Hoptman MJ, Foxe JJ, Saccente E, Wylie GR, Nierenberg J, Jalbrzikowski M, Lim KO, Javitt DC. The neural substrates of impaired prosodic detection in schizophrenia and its sensorial antecedents. Am J Psychiatry. 2007 Mar 1;164(3):474-82. Abstract

Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med. 2007 Sep 1;13(9):1102-7. Abstract

Rorick-Kehn LM, Johnson BG, Burkey JL, Wright RA, Calligaro DO, Marek GJ, Nisenbaum ES, Catlow JT, Kingston AE, Giera DD, Herin MF, Monn JA, McKinzie DL, Schoepp DD. Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039). J Pharmacol Exp Ther. 2007 Apr 1;321(1):308-17. Abstract

Sarihi A, Jiang B, Komaki A, Sohya K, Yanagawa Y, Tsumoto T. Metabotropic glutamate receptor type 5-dependent long-term potentiation of excitatory synapses on fast-spiking GABAergic neurons in mouse visual cortex. J Neurosci. 2008 Jan 30;28(5):1224-35. Abstract

View all comments by Dan Javitt

Related News: Learning from Drug Candidates—New Kid Targets Same Block

Comment by:  Henry Holcomb
Submitted 15 November 2008
Posted 15 November 2008

Homayoun and Moghaddam (PNAS) present important new data concerning the glutamatergic system and psychosis. They suggest the orbital frontal cortex (OFC) is particularly important in the pathophysiology of schizophrenia. They show that treatment with an NMDA receptor (NMDAR) antagonist induces OFC pyramidal neuron hyperactivity (secondary to GABA interneuron hypoactivity). This was reversed with haloperidol, clozapine, and a selective mGlu2/3 agonist, LY354740. This brief essay emphasizes how their findings support hypotheses of a common pathway in the biology of psychotic disorders. This group’s work (Adams et al., 2001; Moghaddam and Adams, 1998) contributes to an extensive body of research on the biology of psychosis. Human research shows that extensive frontal cortical systems and diverse molecular interactions may converge to form a common pathway to produce psychosis.

In their formulations of schizophrenia, Olney (Olney and Farber, 1995), Farber (Farber et al., 2002), and Tamminga (Tamminga et al., 1987) suggested a prominent role for disturbed glutamatergic neurotransmission. Human neurometabolic imaging studies using the NMDAR antagonist ketamine subsequently demonstrated marked brain metabolic hyperactivity. Using blood flow and glucose utilization as surrogate markers of neural activity investigators characterized the brain response to intravenous ketamine administration (Breier et al., 1997; Holcomb et al., 2005; Lahti et al., 1995; Vollenweider et al., 1997). Frontal and anterior cingulate (rostral component) regions of healthy volunteers and schizophrenic participants became hypermetabolic. But it is important to note that hypermetabolic response patterns are also generated in other human, psychotogenic drug models of psychosis. These include high dose amphetamine (Vollenweider et al., 1998), psilocybin (Gouzoulis-Mayfrank et al., 1999; Vollenweider et al., 1997), and cannabis (Mathew et al., 1989; O'Leary et al., 2007).

There is now compelling evidence to directly link cortical metabolic patterns to cortical glutamate/glutamine dynamics (Rothman et al., 1999). Rowland and colleagues’ magnetic resonance spectroscopy (MRS) study of ketamine given to healthy volunteers demonstrated a significant elevation in rostral anterior cingulate glutamine, a putative marker of increased glutamate release (Rowland et al., 2005). It seems reasonable to interpret Theberge and colleagues’ MRS study of never treated schizophrenia (Theberge et al., 2002) as a chemical confirmation of Soyka’s neurometabolic study, also of unmedicated schizophrenic patients (Soyka et al., 2005). Theberge found elevated glutamine in the anterior cingulate. Soyka found elevated glucose utilization in the frontal cortex. These studies, taken together, implicate increased glutamate release as a common mechanism in the pathology of early schizophrenia. Psychosis may arise from NMDA receptor antagonism (ketamine and PCP), stimulation of the 5-HT 2A-mGluR2 complex (psilocybin), or direct stimulation of the CB1 receptor on GABA interneurons (Katona and Freund, 2008). In each instance the consequence is an acute and robust glutamate release caused by disinhibition of pyramidal neurons.

Though Homayoun and Moghaddam have provided an elegant description of this phenomenon in the OFC, it is likely to be equally important in the medial and dorsolateral prefrontal cortex, as well as the anterior cingulate cortex. But the methodology and theory of this paper should help clinical investigators. The thoughtful study of metabotropic glutamatergic receptors and their clinical application (Patil et al., 2007) will go far to illuminate the subtle pathophysiology of psychosis.

References:

1. Adams BW, Moghaddam B: Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex. Biol. Psychiatry 2001; 50:750-757. Abstract

2. Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D: Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am. J. Psychiatry 1997; 154:805-811. Abstract

3. Farber NB, Kim SH, Dikranian K, Jiang XP, Heinkel C: Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity. Mol. Psychiatry 2002; 7:32-43. Abstract

4. Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC: Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 2008; 452:93-97. Abstract

5. Gouzoulis-Mayfrank E, Schreckenberger M, Sabri O, Arning C, Thelen B, Spitzer M, Kovar KA, Hermle L, Bull U, Sass H: Neurometabolic effects of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine in healthy volunteers. A double-blind, placebo-controlled PET study with [18F]FDG. Neuropsychopharmacology 1999; 20:565-581. Abstract

6. Holcomb HH, Lahti AC, Medoff DR, Cullen T, Tamminga CA: Effects of noncompetitive NMDA receptor blockade on anterior cingulate cerebral blood flow in volunteers with schizophrenia. Neuropsychopharmacology 2005; 30:2275-2282. Abstract

7. Katona I, Freund TF: Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat. Med. 2008; 14:923-930. Abstract

8. Lahti AC, Holcomb HH, Medoff DR, Tamminga CA: Ketamine activates psychosis and alters limbic blood flow in schizophrenia. Neuroreport 1995; 6:869-872. Abstract

9. Mathew RJ, Wilson WH, Tant SR: Acute changes in cerebral blood flow associated with marijuana smoking. Acta Psychiatr. Scand. 1989; 79:118-128. Abstract

10. Moghaddam B, Adams BW: Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 1998; 281:1349-1352. Abstract

11. O'Leary DS, Block RI, Koeppel JA, Schultz SK, Magnotta VA, Ponto LB, Watkins GL, Hichwa RD: Effects of smoking marijuana on focal attention and brain blood flow. Hum. Psychopharmacol. 2007; 22:135-148. Abstract

12. Olney JW, Farber NB: NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia. Neuropsychopharmacology 1995; 13:335-345. Abstract

13. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD: Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat. Med. 2007; 13:1102-1107. Abstract

14. Rothman DL, Sibson NR, Hyder F, Shen J, Behar KL, Shulman RG: In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics. Philos. Trans. R. Soc. Lond B Biol. Sci. 1999; 354:1165-1177. Abstract

15. Rowland, L. M., Bustillo, J. R., Mullins, P. G., Jung, R. E., Lenroot, R., Landgraf, E., Barrow, R, Yeo, R, Lauriello, J, and Brooks, W. M. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T Proton MRS study. Am. J. Psychiatry 162(2), 394-396. 2005. Abstract

16. Soyka M, Koch W, Moller HJ, Ruther T, Tatsch K: Hypermetabolic pattern in frontal cortex and other brain regions in unmedicated schizophrenia patients. Results from a FDG-PET study. Eur. Arch. Psychiatry Clin.Neurosci. 2005; 255:308-312. Abstract

17. Tamminga CA, Tanimoto K, Kuo S, Chase TN, Contreras PC, Rice KC, Jackson AE, O'Donohue TL: PCP-induced alterations in cerebral glucose utilization in rat brain: blockade by metaphit, a PCP-receptor-acylating agent. Synapse 1987; 1:497-504. Abstract

18. Theberge J, Bartha R, Drost DJ, Menon RS, Malla A, Takhar J, Neufeld RW, Rogers J, Pavlosky W, Schaefer B, Densmore M, Al Semaan Y, Williamson PC: Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. Am. J. Psychiatry 2002; 159:1944-1946. Abstract

19. Vollenweider FX, Leenders KL, Scharfetter C, Antonini A, Maguire P, Missimer J, Angst J: Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Eur. Neuropsychopharmacol. 1997; 7:9-24. Abstract

20. Vollenweider FX, Leenders KL, Scharfetter C, Maguire P, Stadelmann O, Angst J: Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology 1997; 16:357-372. Abstract

21. Vollenweider FX, Maguire RP, Leenders KL, Mathys K, Angst J: Effects of high amphetamine dose on mood and cerebral glucose metabolism in normal volunteers using positron emission tomography (PET). Psychiatry Res. 1998; 83:149-162. Abstract

View all comments by Henry Holcomb

Related News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  David J. Porteous, SRF Advisor
Submitted 11 February 2009
Posted 12 February 2009

The answer is unequivocally, “yes”
In co-highlighting the papers from Need et al., 2009, and Tomppo et al., 2009, you pose the question “CNV’s, interacting loci or both?” to which my immediate answer is an unequivocal “yes,” but it actually goes further than that. These two studies, interesting in their own rights, add just two more pieces of evidence now accumulated from case only, case-control, and family-based linkage on the genetic architecture of schizophrenia. Thus, we can reject with confidence a single evolutionary and genetic origin for schizophrenia. If it were so, it would have been found already by the plethora of genomewide studies now completed, studies specifically designed to detect causal variants, should they exist, which are both common to most if not all subjects and ancient in origin—the Common Disease, Common Variant (CDCV) hypothesis.

Moreover, for DISC1, NRG1, NRXN1, and a few others, the criteria for causality are met in some subjects, but none of these is the sole cause of schizophrenia. Their net contributions to individual and population risk remain uncertain and await large scale resequencing as well as SNP and CNV studies to capture the totality of genetic variation and how that contributes to the incidence of major mental illness. Meanwhile, nosological and epidemiological evidence has also forced a re-evaluation of the categorical distinction between schizophrenia and bipolar disorder, let alone schizoaffective disorder (Lichtenstein et al., 2009).

In this regard, DISC1 serves again as an instructive paradigm, with good evidence for genetic association to schizophrenia, BP, schizoaffective disorder, and beyond (Chubb et al., 2008). The study by Hennah et al. (2008) added a further nuance to the DISC1 story by demonstrating intra-allelic interaction. Tomppo et al. (2009) now build upon their earlier evidence to show that DISC1 variants affect subcomponents of the psychiatric phenotype, treated now as a quantitative than a dichotomous trait. In much the same way and just as would be predicted, DISC1 variation also contributes to normal variation in human brain development and behavior (e.g., Callicott et al., 2005). Self-evidently, different classes of genetic variants (SNP or CNV, regulatory or coding) will have different biological and therefore psychiatric consequences (Porteous, 2008).

That Need et al. (2009) failed to replicate previous genomewide association studies (or find support for DISC1, NRG1, and the rest) is just further proof, if any were needed, that there is extensive genetic heterogeneity and that common variants of ancient origin are not major determinants of individual or population risk (Porteous, 2008). Variable penetrance, expressivity, and gene-gene interaction (epistasis) all need to be considered, but these intrinsic aspects of genetic influence are best addressed by family studies (currently lacking for CNV studies) and poorly addressed by large-scale case-control genomewide association studies. Power to test the CDCV hypothesis may increase with increasing numbers of subjects, but so does the inherent heterogeneity, both genetic and diagnostic.

That said, genetics is without doubt the most incisive tool we have to dissect the etiology of major mental illness. The criteria for success (and certainly for causality, rather than mere correlation) must be less about the number of noughts after the “p” and much more about the connection between candidate gene, gene variant, and the biological consequences for brain development and function. In this regard, both studies have something to say and offer.

References:

Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. 2009 Lancet 373:234-9. Abstract

Chubb JE, Bradshaw NJ, Soares DC, Porteous DJ, Millar JK. Mol Psychiatry. The DISC locus in psychiatric illness. 2008 Jan;13(1):36-64. Epub 2007 Oct 2. 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. 2005 Proc Natl Acad Sci U S A. 2005 102:8627-32. Abstract

Porteous D. Genetic causality in schizophrenia and bipolar disorder: out with the old and in with the new. 2008 Curr Opin Genet Dev. 18:229-34. Abstract

View all comments by David J. Porteous

Related News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  Pamela DeRosse, Anil Malhotra (SRF Advisor)
Submitted 19 February 2009
Posted 22 February 2009

The results reported by Tomppo et al. and Need et al. collectively instantiate the complexities of the genetic architecture underlying risk for psychiatric illness. Paradoxically, however, while the results of Need et al. suggest that the answer to the complex question of risk genes for schizophrenia (SZ) may be found by searching a very select population for rare changes in genetic sequence, the results of Tomppo et al. suggest that the answer may be found by searching for common variants in large heterogeneous populations. So which is it? Is SZ the result of rare, novel genetic mutations or an accumulation of common ones? Such a conundrum is not a novel predicament in the process of scientific inquiry and such conundrums are often resolved by the reconciliation of both opposing views. Thus, if we allow history to serve as our guide it seems reasonable that the answer to the current question of what genetic mechanisms are responsible for SZ, is that SZ is caused by both rare and common variants.

Although considerable efforts, by our lab and others, are currently being directed towards seeking the type of rare variants that Need et al. suggest may be responsible for risk for SZ, a less concerted effort is being directed towards parsing the effects of more specific, common genetic variations. To date, there are limited data seeking to elucidate the effects of previously identified risk variants for SZ on phenotypic variation within the diagnostic group. The data that are available, however, suggest that risk variants do influence phenotypic variation. Our work with DISC1, for example, has produced relatively robust, and replicated findings linking variation in the gene to cognitive dysfunction (Burdick et al., 2005) as well as an increased risk for persecutory delusions in SZ (DeRosse et al., 2007). Similarly, our work with DTNBP1 indicates a strong association between variants in the gene and both cognitive dysfunction (Burdick et al., 2006) and negative symptoms in SZ (DeRosse et al., 2006). Moreover, the risk for cognitive dysfunction associated with the DTNBP1 risk genotype was also observed in a sample of healthy individuals. Thus, it seems conceivable that genetic variation associated with phenotypic variation within a diagnostic group may also be associated with similar, sub-syndromal phenotypes in non-clinical samples.

The data reported by Tomppo et al. provide support for the utility of parsing the specific effects of genetic variants on phenotypic variation and extend this approach to populations with sub-syndromal psychiatric symptoms. Such an approach is attractive in that it allows us to study the effects of genotype on phenotype without the confound imposed by psychotropic medications. Although the current data linking genes to specific dimensions of psychiatric illness are provocative, the study groups utilized are comprised of patients undergoing varying degrees of pharmacological intervention. Thus, in these analyses quantitative assessment of psychosis is to some extent confounded by treatment history and response. By measuring lifetime history of symptoms, which for most patients includes substantial periods without effective medication, many studies (including our own) may partially overcome this limitation. Still, assessment of the relation between genetic variation and dimensions of psychosis in study groups not undergoing treatment with pharmacological agents would be a compelling source of confirmation for these preliminary findings.

Perhaps most importantly, the data reported by Tomppo et al. suggest that previously identified risk genes should not be marginalized but rather, should be studied in non-clinical samples to identity phenotypic variation that may be related to the signs and symptoms of psychiatric illness.

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):1399-402. Abstract

Burdick KE, Lencz T, Funke B, Finn CT, Szeszko PR, Kane JM, Kucherlapati R, Malhotra AK. Genetic variation in DTNBP1 influences general cognitive ability. Hum Mol Genet. 2006; 15(10):1563-8. Abstract

DeRosse P, Hodgkinson CA, Lencz T, Burdick KE, Kane JM, Goldman D, Malhotra AK. Disrupted in schizophrenia 1 genotype and positive symptoms in schizophrenia. Biol Psychiatry. 2007; 61(10):1208-10. Abstract

DeRosse P, Funke B, Burdick KE, Lencz T, Ekholm JM, Kane JM, Kucherlapati R, Malhotra AK. Dysbindin genotype and negative symptoms in schizophrenia. Am J Psychiatry. 2006; 163(3):532-4. Abstract

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Related News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  James L. Kennedy, SRF Advisor (Disclosure)
Submitted 25 February 2009
Posted 25 February 2009

Has anyone considered the possibility that the CNVs found to be elevated in schizophrenia versus controls could be a peripheral effect and perhaps not present in brain tissue? For example, the diet of the typical schizophrenia patient is poor, and it is conceivable that chronic folate deficiency could predispose to problems in DNA structure or repair in lymphocytes. Thus, the CNVs could be an effect of the illness, and not a cause. Someone needs to do the experiment that compares CNVs in blood to those in the brain of the same individual. And then we need studies of the stability of CNVs over the lifetime of an individual.

View all comments by James L. Kennedy

Related News: Copy-number Variants, Interacting Alleles, or Both?

Comment by:  Kevin J. Mitchell
Submitted 2 March 2009
Posted 2 March 2009

The papers by Need et al. and Tomppo et al. seem to present conflicting evidence for the involvement of common or rare variants in the etiology of schizophrenia.

On the one hand, Need et al., in a very large and well-powered sample, find no evidence for involvement of any common SNPs or CNVs. Importantly, they show that while any one SNP with a small effect and modest allelic frequency might be missed by their analysis, the likelihood that all such putative SNPs would be missed is vanishingly small. They come to the reasonable conclusion that common variants are unlikely to play a major role in the etiology of schizophrenia, except under a highly specific and implausible genetic model. Does this sound the death knell for the common variants, polygenic model of schizophrenia? Yes and no. These and other empirical data are consistent with theoretical analyses which show that the currently popular purely polygenic model, without some gene(s) of large effect, cannot explain familial risk patterns (Hemminki et al., 2007; Hemminki et al., 2008; Bodmer and Bonilla, 2008). It has been suggested that epistatic interactions may generate discontinuous risk from a continuous distribution of common alleles; however, while comparisons of risk in monozygotic and dizygotic twins are consistent with some contribution from epistasis, they are not consistent with the massive levels that would be required to rescue a purely polygenic mechanism, whether through a multiplicative or (biologically unrealistic) threshold model.

Thus, it seems most parsimonious to conclude that most cases of schizophrenia will involve a variant of large effect. As such variants are likely to be rapidly selected against, they are also likely to be quite rare. The findings of specific, gene-disrupting CNVs or mutations in individual genes in schizophrenia cases by Need et al. and numerous other groups support this idea. Excitingly, they also have highlighted specific molecules and biological pathways that provide molecular entry points to elucidate pathogenic mechanisms. The possible convergence on genes interacting with DISC1, including PCM1 and NDE1 in the current study, provides further support for the importance of this pathway, though, clearly, there may be many other ways to disrupt neural development or function that could lead to schizophrenia. (Conversely, it is becoming clearer that many of the putative causative mutations identified so far predispose to multiple psychiatric or neurological conditions.)

Despite the likely involvement of rare variants in most cases of schizophrenia, it remains possible that common alleles could have a modifying influence on risk—indeed, one early paper commonly cited as supporting a polygenic model for schizophrenia actually provided strong support for a model of a single gene of large effect and two to three modifiers (Risch, 1990). A rare variants/common modifiers model would be consistent with the body of literature on modifying genes in model organisms, where effects of genetic background on the phenotypic expression of particular mutations are quite common and can sometimes be large (Nadeau, 2001). Whether such genetic background effects would be mediated by common or rare variants is another question—there is certainly good reason to think that rare or even private mutations may make a larger contribution to phenotypic variance than previously suspected (Ng et al., 2008; Ji et al., 2008).

Nevertheless, common variants are also likely to be involved, and these effects might be detectable in large association studies, though they would be expected to be diluted across genotypes. This might explain inconsistent findings of association of common variants with disease state for various genes, including COMT, BDNF, and DISC1, for example. This issue has led some to look for association of variants in these genes with endophenotypes of schizophrenia in the general population—psychological or physiological traits that are heritable and affected by the symptoms of the disease, such as working memory, executive function, or, in the study by Tomppo et al., social interaction.

These approaches have tended to lead to statistically stronger and more consistent associations and are undoubtedly revealing genes and mechanisms contributing to normal variation in many psychological traits. How this relates to their potential involvement in disease etiology is far from clear, however. The implication of the endophenotype model is that the disorder itself emerges due to the combination of minor effects on multiple symptom parameters (Gottesman and Gould, 2003; Meyer-Lindenberg and Weinberger, 2006). An alternative interpretation is that these common variants may modify the phenotypic expression of some other rare variant, either due to their demonstrated effect on the psychological trait in question or through a more fundamental biochemical interaction, but that in the absence of such a variant of large effect, no combination of common alleles would lead to disease.

References:

Hemminki K, Försti A, Bermejo JL. The 'common disease-common variant' hypothesis and familial risks. PLoS ONE. 2008 Jun 18;3(6):e2504. Abstract

Hemminki K, Bermejo JL. Constraints for genetic association studies imposed by attributable fraction and familial risk. Carcinogenesis. 2007 Mar;28(3):648-56. Abstract

Bodmer W, Bonilla C. Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet. 2008 Jun;40(6):695-701. Abstract

Risch N. Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet. 1990 Feb;46(2):222-8. Abstract

Nadeau JH. Modifier genes in mice and humans. Nat Rev Genet. 2001 Mar;2(3):165-74. Abstract

Ng PC, Levy S, Huang J, Stockwell TB, Walenz BP, Li K, Axelrod N, Busam DA, Strausberg RL, Venter JC. Genetic variation in an individual human exome. PLoS Genet. 2008 Aug 15;4(8):e1000160. Abstract

Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008 May;40(5):592-9. Abstract

Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003 Apr;160(4):636-45. Abstract

Meyer-Lindenberg A, Weinberger DR. Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci. 2006 Oct;7(10):818-27. Abstract

View all comments by Kevin J. Mitchell

Related News: DISC1 Players Gird For Adult Neurodevelopment

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. Mitchell

Related News: DISC1 Players Gird For Adult Neurodevelopment

Comment by:  Peter Penzes, Michael 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.

References:

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

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