Schizophrenia Research Forum - A Catalyst for Creative Thinking

Timing is Everything—Perinatal DISC1 and Later Behavior Changes

21 January 2010. Disrupted in schizophrenia 1 (DISC1) is one of the most promising schizophrenia gene candidates, but exactly how it might increase susceptibility to the disease is unclear. One theory is that mutations suppress the gene, causing early developmental problems that predispose to the later emergence of symptoms. An alternative hypothesis is that those developmental problems are caused not by loss of the protein but by DISC1 protein fragments that block the function of the normal protein. New research supports the latter interpretation and also emphasizes that the timing of DISC1 gene activity could be a crucial factor in the disease. In the January 5 Molecular Psychiatry online, researchers led by Mikhail Pletnikov at Johns Hopkins University School of Medicine, Baltimore, Maryland, report that overproduction of DISC1 at various times during mouse brain development can precipitate different behaviors that may model vulnerability to schizophrenia or depression.

DISC1 was first discovered in an extended Scottish family. A mutation, specifically the replacement of a section of chromosome 1 with DNA from chromosome 11, interrupts the gene and truncates the protein product. The smaller DISC1 is rapidly degraded in some cells, but it is not clear if it is stable enough in neurons to have a physiological role. The new findings support the idea that truncated DISC1 fragments may act as dominant-negative suppressors of normal DISC1 activity in the brain.

To test the dominant-negative theory, Pletnikov and colleagues generated a mouse model in which overexpression of a truncated human DISC1 mutant (hDISC1) is regulated by an inducible promoter system that can be turned off. Previously, these researchers reported that keeping the promoter on throughout development can lead to schizophrenia-like behavioral symptoms (see SRF related news story). In this study they examined the effects of having the gene turned on or off at specific times during development. First author Yavuz Ayhan and colleagues looked at four different expression patterns: hDISC1 expressed prenatally, postnatally, both, and not at all. They found that morphological and behavioral abnormalities that ensued depended on when hDISC1 overexpression was initiated. The outcomes were also different in male and female animals.

Ayhan and colleagues report that the most robust effects were seen when hDISC1 expression occurred both pre- and postnatally. Under this scenario, three- to seven-month-old male mice were more aggressive than control animals and were more sensitive to NMDA glutamate receptor antagonists and amphetamines, which can induce psychosis-like behavior in humans and are often used in animals to model aspects of schizophrenia. Male mice also had reduced levels of dopamine in the brain. Female mice showed no aggressive characteristics but did have an increased propensity for depression. These behavioral changes were accompanied by gross anatomical changes in both male and female mice. Lateral ventricles, which are consistently enlarged, on average, in schizophrenia patients, were bigger in the animals, and there was reduced cortical volume. The number of parvalbumin-positive neurons was decreased in frontal, temporal, and parito-occipital cortices. Synaptic density in the dentate gyrus was increased.

Only some of these abnormalities were seen when hDISC1 expression was limited to pre- or postnatal periods alone. When expressed after birth, hDISC1 caused male mice to exhibit less non-aggressive social behavior but no increase in aggressive behavior. Female mice were also more susceptible to depression. Lateral ventricles were increased and cortical volume reduced as when hDISC1 was expressed pre- and postnatally, but the reduction in parvalbumin-positive interneurons was restricted to the frontal and parito-occipital cortices. There was a reduction in dopamine in the brains of both male and female mice. Expressed only before birth, hDISC1 had no effect on subsequent behavior, and there was no change in lateral ventricle or cortex volumes. Reductions in parvalbumin-positive neurons was restricted to the frontal cortex alone, and dopamine was reduced in only male mice. Interestingly, there was a reduction in overall brain volume in these mice that was not seen when hDISC1 was overexpressed during the other time periods, and there was an increase in synaptic density in the cortex that was specific to mice expressing hDISC1 prenatally as well.

“The primary conclusion of our study is that the effects of mutant hDISC1 are qualitatively and quantitatively different, depending on when during neurodevelopment the protein is expressed,” write the authors. How the work relates to schizophrenia or the other psychiatric disorders linked to the gene is not fully clear, but the authors note that the translocation in the human gene has been linked to diverse clinical manifestations which may relate to timing of expression. Previously, early postnatal, but not adult, expression of a C-terminal portion of DISC1 was shown to cause phenotypes that included depression, reduced sociability, and poor spatial working memory (see SRF related news story). Interestingly, in contrast to Pletnikov’s model, C-terminal DISC1 also caused reduced dendritic complexity in this earlier study.

Several other models have also been reported. In general, the models show similar behavioral and morphological abnormalities, though there are some differences. In Pletnikov’s model, as well as two single point mutation mouse models (see SRF related news story), and another model that expresses a truncated DISC1 (see Shen et al., 2008), the lateral ventricles are increased in size. In the latter model, parvalbumin-positive neurons are also sparse compared to control mice. The point mutation models also lead to depression-like symptoms and aberrant social behavior, and seem unique in causing deficiencies in prepulse inhibition, a phenomenon that is often compromised in patients with schizophrenia. All told, the varying models of DISC1 function support the idea that early neurodevelopmental problems can predispose people to schizophrenia and other major neuropsychiatric disorders, such as depression. These mouse models may prove useful in figuring out how to find treatments for later symptoms.—Tom Fagan.

Reference:
Ayhan Y, Abazyan B, Nomura J, Kim R, Ladenheim B, Krasnova IN, Sawa A, Margolis RL, Cadet JL, Mori S, Vogel MW, Ross CA, Pletnikov MV. Differential effects of prenatal and postnatal expressions of mutant human DISC1 on neurobehavioral phenotypes in transgenic mice: evidence for neurodevelopmental origin of major psychiatric disorders. Mol Psychiatry. 2010 Jan 5. Abstract

Comments on Related News


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: Inducing Schizophrenic Behavior? Researchers Roll Out New DISC1 Mouse

Comment by:  John RoderSteven Clapcote
Submitted 17 September 2007
Posted 17 September 2007

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

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

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

The behavioral phenotype was similar to the recent paper from the Sawa group (Hikida et al., 2007) in that it also analyzed a transgenic mouse expressing the same C-terminal truncation of the human DISC1 gene, using the same CaMKII promoter. An important difference in the findings was a reduction of murine DISC1 (50 percent at protein level) in the Pletnikov et al. mice but none in the Sawa group mice. This issue is important because of a recent paper in Cell by the Song group (Duan et al., 2007). In that paper, RNAi was used to reduce wild-type native murine DISC1. Individual neurons with targeted DISC1 knockdown showed accelerated neurite development, greater synapse formation and enhanced excitability. Hippocampal granule cells showed accelerated morphological integration resulting in mispositioning. Unfortunately, in the Song paper they analyzed only cells with complete or no knockdown of DISC1. Partial knockdown vectors were made that achieved 75 percent reduction at the protein level but were not analyzed. Only then would it be possible to compare these morphological data with those from Pletnikov et al., which was a 50 percent reduction. Another difference was that the Song group found that DISC1 needed to interact with Nudel. Pletnikov et al. found normal levels of Nudel in the mice but lower LIS1, which could explain the brain development phenotype.

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Related News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

Comment by:  John Roder
Submitted 30 November 2007
Posted 30 November 2007

Some observations on the new report by Li and colleagues: this work is the first to map subregions of DISC1 and to show that a region that binds Nudel and LIS1 is important in generating schizophrenia-like perturbations in vivo. The authors express DISC1 C-terminus in mice, which interacts with Nudel and LIS1. They showed less native mouse DISC1 associations with Nudel mouse following gene induction. This suggests a dominant-negative mechanism.

No data was shown on native DISC1 levels following induction. Work from the Sawa lab shows that if murine DISC1 levels are reduced in non-engineered mice using RNAi, severe perturbations in development of nervous system are seen (Kamiya et al., 2005); however, behavior was not measured in this study. Severe perturbations would be expected based on the neonatal ventral hippocampal lesion model. In this latter model early brain lesions lead to later impairments in PPI and other behaviors consistent with schizophrenic-like behavior.

They use a promoter only expressed in the forebrain, so it is puzzling they see expression in the cerebellum. Expressed DISC1 bound to endogenous mouse Nudel and LIS1, presumably exerting a dominant-negative effect. Induction of the C-terminus DISC1 at day 7, but not in the adult, led to deficits in working memory, the forced swim test, and sociability. It would have been reassuring if these tasks were validated using antipsychotics and antidepressants. It is not clear in this study why the female C57 was used as a standard opponent mouse, and what genders of DISC1 mice have been used. Even though young C57 females (6 weeks old) were used as neutral partners, the data might be interpreted also as impaired sexual motivation in DISC1-Tg-Tm7 mice.

The authors made an attempt to translate their mouse data (low sociability) into a human population and found an association between DISC1 haplotypes and social impairments in a Finnish population (n = 232 samples), which supports a DISC1 role in social behavior, one of schizophrenia's symptoms. It would be useful to distinguish deficits in social interactions and impaired sexual behavior.

Deficits in working memory are also an important schizophrenia endophenotype, and it would be interesting to measure how specific the cognitive deficit is in DISC1-Tg-Tm-7 mice, estimating associative memory in classical fear conditioning, for example.

Induction of the transgene early in development to day 7 resulted in small changes in dendritic complexity in granule cells in the dentate gyrus. It is surprising larger changes were not observed. The role of DISC1 in the adult self-renewing progenitor cells in the dentate switches, so that DISC1 acts as a brake for dendritic complexity and migration (Duan et al., 2007). Thus, reductions in DISC1 in the adult dentate gyrus granule cells lead to enhanced dendrite growth/complexity.

In the adult, DISC1 was shown to interact with Nudel in controlling adult neurogenesis and development. It is of interest that in the Li et al. paper the transgene also perturbs native DISC1 binding to Nudel at day 7 but not adult. Synaptic transmission was reduced in CA1. It would have been nice to see a recording from dentate granule cells in which changes in dendritic complexity were found.

References:

Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U, Kudo C, Okawa M, Ross CA, Hatten ME, Nakajima K, Sawa A. A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development. Nat Cell Biol. 2005 Dec 1;7(12):1167-78. Abstract

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

View all comments by John Roder

Related News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

Comment by:  Akira Sawa, SRF Advisor
Submitted 3 December 2007
Posted 3 December 2007

DISC1 may be a promising entry point to explore important disease pathways for schizophrenia and related mental conditions; thus, animal models that can provide us with insights into the pathways involving DISC1 may be helpful. In this sense, the new animal model reported by Li et al. (Silva and Cannon’s group at UCLA) has great significance in this field.

They made mice expressing a short domain of DISC1 that may block interaction of DISC1 with a set of protein interactors, including NUDEL/NDEL1 and LIS1. This approach, if the domain is much shorter, will be an important methodology in exploring the disease pathways based on protein interactions. Although the manuscript is excellent, and appropriate as the first report, the domain expressed in the transgenic mice can interact with more than 30-40 proteins, and the phenotypes that the authors observed might not be attributable to the disturbance of protein interactions of DISC1 and NUDEL or LIS1.

Now we have at least five different types of animal models for DISC1, all of which have unique advantages and disadvantages: 1) mice with a spontaneous mutation in an exon, which seem to lack some, but not all, DISC1 isoforms, from Gogos’s lab (see Koike et al., 2006; Ishizuka et al., 2007); 2) mice with mutations induced by a mutagen from Roder’s lab (Clapcote et al., 2007); 3) transgenic mice that express a dominant-negative mutant DISC1 from Sawa’s lab (Hikida et al., 2007); 4) transgenic mice that express a dominant-negative mutant DISC1 in an inducible manner from Pletkinov’s lab (Pletnikov et al., 2007); and 5) the mice from Silva’s and Cannon’s labs.

It is impossible to reach a firm conclusion on how the Scottish mutation of the DISC1 gene leads to molecular dysfunction until the data from autopsied brains of patients in the Scottish family become available. Millar and colleagues have published data of DISC1 in lymphoblastoid cells from the family members and propose an intriguing suggestion of how DISC1 is potentially disturbed in the pedigree (Millar et al., 2005); however, this remains in the realm of hypothesis/suggestion from peripheral cells. Thus, it is very important to compare the various types of DISC1 animal models in approaching how disturbance of DISC1 in brain leads to the pathophysiology of schizophrenia and related disorders.

References:

Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3693-7. Abstract

Ishizuka K, Chen J, Taya S, Li W, Millar JK, Xu Y, Clapcote SJ, Hookway C, Morita M, Kamiya A, Tomoda T, Lipska BK, Roder JC, Pletnikov M, Porteous D, Silva AJ, Cannon TD, Kaibuchi K, Brandon NJ, Weinberger DR, Sawa A. Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Mol Psychiatry. 2007 Oct ;12(10):897-9. Abstract

Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, Lerch JP, Trimble K, Uchiyama M, Sakuraba Y, Kaneda H, Shiroishi T, Houslay MD, Henkelman RM, Sled JG, Gondo Y, Porteous DJ, Roder JC. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron. 2007 May 3;54(3):387-402. Abstract

Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue R, Andradé M, Tankou S, Mori S, Gallagher M, Ishizuka K, Pletnikov M, Kida S, Sawa A. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14501-6. Abstract

Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, Mori S, Moran TH, Ross CA. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2007 Sep 11; Abstract

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

View all comments by Akira Sawa

Related News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

Comment by:  David J. Porteous, SRF Advisor
Submitted 21 December 2007
Posted 22 December 2007

On the DISC1 bus
You wait ages for a bus, then a string of them come one behind the other. First, Koike et al. (2006) reported that the 129 strain of mouse had a small detection of the DISC1 gene and this was associated with a deficit on a learning task. The interpretation of this observation was somewhat complicated by the subsequent recognition that the majority, if not all, major DISC1 isoforms are unaffected by the deletion, but this needs further work (Ishizuka et al., 2007). Then, Clapcote et al. (2007) provided a very detailed characterization of two independent ENU-induced mouse missense mutations of DISC1, showing selective brain shrinkage and marked behavioral abnormalities that in one mutant were schizophrenia-like, the other more akin to mood disorder. Importantly, these phenotypes could be differentially rescued by antipsychotics or antidepressants. The main finger pointed to disruption of the interaction with PDE4 to misregulate cAMP signaling (Millar et al., 2005; Murdoch et al., 2007).

Then, back-to-back came two variants of DISC1 transgenic models from Johns Hopkins University (Pletnikov et al., 2007; Hikida et al., 2007) (see also SCZ Forum). Both Pletnikov and Hikida overexpressed a truncated form of DISC1 under the control of the CaMKII promoter (in Pletnikov’s case with an inducible CaMKU promoter). Both groups reported brain structural and behavioral abnormalities that aligned rather nicely with the earlier work of Clapcote et al. (2007). Pletnikov et al. showed that neurite outgrowth was attenuated in primary cortical neurons. They also showed that endogenous DISC1, LIS1, and SNAP25, but not NDEL1 or PSD-95, was reduced in mouse forebrain.

Now, Li et al. (2007) introduce yet another transgenic DISC1 model mouse, this time overexpressing a carboxy tail fragment of DISC1, so the opposite end of the DISC1 molecule from that overexpressed by Pletnikov and by Hikida. Intriguingly, Li et al. (as with all the preceding models) report significant behavioral differences for wild-type littermates. The point of added interest and significance here is that by using an inducible transgenic construct, they could elicit behavioral abnormalities if carboxy terminal DISC1 was expressed on postnatal day 7 only, but not in adult life. What are we to make of this and how do the models align? Li et al. interpret their results to suggest that DISC1 plays a crucial role, through NDEL1 and LIS1, in postnatal (but not adult) brain development. This study obviously raises some key questions. What is the developmental window of DISC1 effect? How can the lack of effect in the adult be reconciled with the rather striking effect on neurogenesis consequent upon downregulation of DISC1 in the adult mouse brain reported by Duan et al. (2007). And if overexpressing 5’ (Hikida, Pletnikov) or 3’ constructs (Li) can elicit similar phenotypes as seen in ENU-induced missense variants within exon 2 (Clapcote), can we come up with a unifying explanation? Perhaps not yet, but these various mouse models certainly emphasize the value of a multi-pronged mouse modeling approach. Combinations of “null,” transgenic, inducible, and missense mutants will help dissect the underlying processes. These studies also suggest that a variety of DISC1 variants in humans might elicit rather similar and also subtly different phenotypes. Indeed, Li et al. try to link their findings on the mouse to human studies, but here I feel there is cause for caution. The genetic association referred to maps to a haplotype in a quite distinct region of DISC1 and the direct or indirect functional effect of the haplotype is far from clear. It is, however, conceptually unlikely that this risk haplotype has a specific or restricted effect on Nudel and/or Lis1 binding. The corollary between a genetic association for a selected, but poorly defined sub-phenotype of schizophrenia with a poorly defined behavioral phenotype in the mouse may be a corollary too far too soon. Finally, whereas the focus of attention by Li, Pletnikov, and Hikida has been on the well-established/neurodevelopmental role of NDEL1 (and LIS1), the potential role of PDE4B both in neurosignaling (related to behavior, learning, and memory) and possibly also neurodevelopment should not be overlooked. In this regard it is noteworthy that PDE4 interacts both with the head and the carboxy tail domain of DISC1 (Hannah et al., 2007) and this most likely contributes to the phenotype in all the models described to date.

References:

Clapcote SJ, Lipina TV, Millar JK, Mackie S, Christie S, Ogawa F, Lerch JP, Trimble K, Uchiyama M, Sakuraba Y, Kaneda H, Shiroishi T, Houslay MD, Henkelman RM, Sled JG, Gondo Y, Porteous DJ, Roder JC. Behavioral phenotypes of Disc1 missense mutations in mice. Neuron. 2007 May 3;54(3):387-402. Abstract

Hikida T, Jaaro-Peled H, Seshadri S, Oishi K, Hookway C, Kong S, Wu D, Xue R, Andradé M, Tankou S, Mori S, Gallagher M, Ishizuka K, Pletnikov M, Kida S, Sawa A. Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14501-6. Abstract

Ishizuka K, Chen J, Taya S, Li W, Millar JK, Xu Y, Clapcote SJ, Hookway C, Morita M, Kamiya A, Tomoda T, Lipska BK, Roder JC, Pletnikov M, Porteous D, Silva AJ, Cannon TD, Kaibuchi K, Brandon NJ, Weinberger DR, Sawa A. Evidence that many of the DISC1 isoforms in C57BL/6J mice are also expressed in 129S6/SvEv mice. Mol Psychiatry. 2007 Oct 1;12(10):897-9. Abstract

Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3693-7. Abstract

Li W, Zhou Y, Jentsch JD, Brown RA, Tian X, Ehninger D, Hennah W, Peltonen L, Lönnqvist J, Huttunen MO, Kaprio J, Trachtenberg JT, Silva AJ, Cannon TD. Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18280-5. Abstract

Millar JK, James R, Christie S, Porteous DJ. Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria. Mol Cell Neurosci. 2005 Dec 1;30(4):477-84. 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

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

Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H, Mori S, Moran TH, Ross CA. Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol Psychiatry. 2007 Sep 11; [Epub ahead of print] Abstract

View all comments by David J. Porteous