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Live Discussion Transcript


Posted 4 June 2010

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Live Discussion: DISC1 Roundtable 2010

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Attendees/Participants

Bagrat Abazyan, John Hopkins University
Nick Bradshaw, University of Edinburgh
Nicholas Brandon, Pfizer Inc.
Gareth Briggs, MMC Edinburgh
Andres Buonanno, National Institute of Child Health and Human Development, NIH
Kafui Dzirasa, Duke University
Angela Epshtein, Schizophrenia Research Forum
Nao J. Gamo, Yale University
Akiko Hayashi, Johns Hopkins University
Hakon Heimer, Schizophrenia Research Forum
Beverly Huang, Johns Hopkins University
Hanna Jaaro-Peled, Johns Hopkins University
Atsushi Kamiya, Johns Hopkins University
Carsten Korth, University of Düsseldorf, Germany
Tatiana Lipina, Samuel Lunenfeld Research Institute
Patricio ODonnell, University of Maryland
Peter Penzes, Northwestern University
David Porteous, University of Edinburgh
Amy Ramsey, University of Toronto.
Akira Sawa, Johns Hopkins University
David St Clair, University of Aberdeen
Rosie Walker, University of Edinburgh
Jon Wood, University of Sheffield

Note: Transcript has been edited for clarity and accuracy.


Akira Sawa
Hello, everybody, this is the third DISC1 roundtable meeting: the first time was in 2008 by David, the second time was in 2009 by Ty, Nick, and myself, and as of January 2010, we have added even more exciting findings, and I believe it is great to have the DISC1 roundtable again today.

Hakon Heimer
My cut and paste doesn't seem to be working so I can't paste in my carefully prepared homages to David and Akira, but I see that Akira is an old hand and has taken charge. Thanks to David and Akira.

Carsten Korth
Hi, Nico, Hi, everybody; thanks to Nico I could circumvent our firewall.

David Porteous
Akira, I think you will lead us off for the first topic. I am very interested to get an update on DISC1 mouse knockout models and their availability. Also rat. And an update on other models, e.g., zebrafish.

Akira Sawa
Certainly. The first topic is on animal models. Several types of animal models in which DISC1 is impaired in many ways have been published. Very interestingly, they show, to some extent, similar phenotypes, which can also be interpreted as possible endophenotypes for mental illnesses. How about having people's frank opinions on the current models? Advantages? Excitements? Limitations?

David Porteous
What is striking to me is how informative each model has turned out to be. Obviously, a true “null” model would be very valuable. Also, regulated expression of DISC1 during development and expression of clinical mutations

Amy Ramsey
I think one of the useful tools has been the conditional DISC1 mutant that Misha Pletnikov made to explore the role of DISC1 at different stages of development.

Akira Sawa
In response to David's question, as we presented at the SfN meeting last year, we have a knockout in collaboration with Toshi Tomoda at City of Hope, California. As far as I know, there are several other groups who are trying to make a knockout. In addition, knockout rats are also being generated in the world. True null is very difficult, as we do not know the full isoforms of DISC1. The only way to make a full knockout is to make a large chromosomal deletion, and in that Allan Bradley at the Sanger Institute has expertise.

David Porteous
Can you share anything on the DISC1 knockout that was not presented at SfN? When can we expect the first published description? When I asked for the true “null” to be made through the Sanger pipeline, it was said to be “too difficult.”

Akira Sawa
A putative true null can be tried, and a conventional knockout can be tried at least, but eventually, as Amy Ramsey mentioned, context-dependent DISC1 null will be tried. David, as for Sanger, Sanger does not have good cell lines to make large deletions only for DISC1; they may include the deletion with adjacent genes.

Amy Ramsey
As much as I think that the null, or null conditional, would be satisfying to see, I think that “rescue” by conditional overexpression of DISC1 would be a benefit to determine whether this is a pharmacological target.

David Porteous
So the current models are great, but limited, and more are needed—true null, regulatable on/off, and clinical mutations.

Nick Bradshaw
Not to mention “rescue” by expression of family translocation-like partial DISC1 gene.

Andres Buonanno
Akira or David, can you clarify, for a non-DISC1 aficionado, if GABAergic interneurons express different transcripts than principal glutamatergic neurons? If so, is anyone making conditionals and targeting DISC1 in specific cells?

Akira Sawa
Andres, this is an outstanding question. This is to be addressed with a conditional knockout. Especially, as DISC1-NRG1 signaling has cross-talk, this question should be very important. Thanks for the very useful comments.

David Porteous
Andres: Sanbing Shen, Nick Bradshaw et al. may be able to say something more about GABAergic interneurons. Certainly Lipska/ Kleinman et al. have added a lot to the DISC1 story with multiple novel isoforms that change over development.

Amy Ramsey
Overexpression is even more difficult because the gene is so big.

David Porteous
Amy, I agree, but my cautionary note would be that we don't want to treat a mouse, we want to treat a patient, and so far as I am aware there is no evidence for overexpression mechanisms for DISC1 in psychopathology.

Akira Sawa
As far as I know, Toshi Tomoda at City of Hope, together with Hanna Jaaro-Peled and Beverly Huang, presented evidence that phenotypes of a putative DISC1 knockout model are rescued by overexpression of full-length wild-type DISC1 under the CaMKII promoter (only expressed after birth in limited neurons), suggesting that we can intervene postnatally with some of the phenotypes occurring before birth.

Amy Ramsey
David P., I was just thinking that maybe we should be seeing if there are drugs that improve DISC1 function, and the overexpressor would be a proof-of-principle mouse to rescue psychosis.

Akira Sawa
Amy and David P., expression level of exogenous protein in transgenic mice differs among lines. In some, there is high expression, but in others very modest expression, with much less than endogenous levels. Thus, exogenous transgenic expression may not be directly associated with artificial overexpression. Thus, we have ways to modulate this issue, as long as we are very cautious, as David P. said.

David Porteous
Amy, agreed, but let’s also keep in mind what we know from human genetics and let’s be clear about what we mean by improving DISC1—what assays are most relevant/practical/feasible? Biochemical or behavioral?

Akira Sawa
David P., both. However, from a more clinical viewpoint, brain imaging or non-invasive electrophysiology is important.

Amy Ramsey
I hope that as we learn more about what DISC1 does and interacts with, we can develop in vitro assays. Perhaps its interactions with PDE4 and NDEL1 are best described?

David Porteous
To Akira and Amy, Will Hennah and I reported effects of very modest downregulation of DISC1 expression and impact on drug target pathways—its going to be subtle, but yes, PDE4 and NDE1/NDEL1 seem to be at the core, plus GSK3β, of course.

Akira Sawa
David, this is very exciting. How about more synaptic interactors? Although PDE4 is also an interesting molecule in the synapse.

David St Clair
Akira, can you say any more about the GABAergic deficit in your mouse?

David Porteous
David St Clair, what more can you say about the GABAergic deficit in your mouse?

Akira Sawa
In transgenic mice expressing C-terminal truncated mutant, decrease in PV staining (consistent with observations in human brains or PCP animal models) is observed. This occurs in your (David St Clair’s) and Misha's models, I believe. One interesting question is, in the case of transgenic mice under CaMKII promoter, how mutant expression in the pyramidal neurons, but not interneurons, finally resulted in interneuron phenotypes.

David St Clair
One of the problems is that the number of synaptic connections is much reduced, so fewer firing sites.

Patricio ODonnell
Amy/David, regarding possible therapeutic targets, we should all keep in mind the developmental aspects of the disease. In other words, a truncated DISC1 (a là Scottish family) would have an impact on cortical circuit development that may become evident in altered function as the brain matures (and I am extending maturation into adolescence here—the time of onset of symptoms). So, I think we need to understand better what are the targets of DISC1 that affect circuit development to identify possible therapeutic avenues.

Akiko Hayashi
I agree with Patricio. I would like to emphasize why the onset of schizophrenia is after adolescence to young adult. It is natural to think something occurring during adolescence triggers schizophrenia onset. There are two possibilities. The first one is that the normal brain development during adolescence unmasks a pre-existing schizophrenia lesion, which is present before birth. The second one is that schizophrenia risk genes predominantly function during adolescence. A promising cellular event which is strongly modified by these two explanations might be synaptic pruning, which robustly takes place during postnatal development. An important point is that synaptic pruning mainly occurs in glutamatergic synapses.

David Porteous
Patricio, agreed—this is at the heart of the problem in schizophrenia, but arguably DISC1 gives us as good a framework as any to understand the developmental aspect and opportunities/windows for effective intervention. Akiko, DISC1 certainly looks to have a multiplicity of functions in neurodevelopment, circuitry, and signaling—any or all may be relevant to pathology, but may differ markedly in terms of therapeutic opportunity.

David St Clair
Akiko, of course the massive brain changes in adolescence may overload the capacity of neurogenesis to keep up in schizophrenia.

Akiko Hayashi
David Porteous, Agreed. But as for a therapeutic target, I think DISC1 function in late development to adult only could be a therapeutic target.

Akira Sawa
As a discussion moderator, two issues. One: in addition to neuronal communications, now Carsten Korth has observed (reported at SfN) glial expression of DISC1. Thus, glial-neuronal communication via DISC1 is also to be considered (see Misha Pletnikov's comment to us before this roundtable). In addition, although we are fully excited about these data, in five minutes or so, we may need to move to the next topic: updates on DISC1 genetics. New information from genetics also assists generation of new animal models.

Carsten Korth
Akira, yes, in human postmortem brains we see DISC1 abundantly expressed in all cell types, including microglia, oligodendroglia, and astrocytes.

David Porteous
Perhaps we should switch our minds to DISC1 genetics—it seems that DISC1 variants play a role in schizophrenia, bipolar, unipolar, autism, and possibly dementia/cognition. Anyone want to comment on that? Also, that there is a spectrum of alternative genetic lesions—coding and non-coding, common and rare. Comments? Updates?

Akira Sawa
I am personally very interested in Dennis Selkoe's report (at SfN) of DISC1-APP interaction, which may also fit with the report from David P. on cognitive aging and DISC1.

Hakon Heimer
We are approaching the last 20 minutes and turning to genetics, but feel free to offer final thoughts on the previous threads of conversation.

David Porteous
Akira, DISC1 was also a possible hit in Pericak-Vance GWAS for Alzheimer’s, and we have evidence for association for cognitive phenotypes.

Hakon Heimer
David P., have you communicated with the folks who do cognition GWAS to see where DISC1 pops up?

Akira Sawa
Hakon and Nico, Now Schizophrenia Research Forum can combine with Alzforum for a discussion of DISC1? Kafui, question: from your expertise viewpoint, which types of dissections are important with different types of DISC1 animals? Your opinion, if you do not mind, will be appreciated by these members....

Kafui Dzirasa
Akira, please clarify what you mean when you say “dissections.”

Akira Sawa
Kafui, assays.

Kafui Dzirasa
Akira, development-wise, location-wise, cell type. I think it is fairly important to understand how the biochemical and structural changes seen in DISC1 mutants alter physiological circuit function. Slice physiological, single unit recordings, and stimulation techniques will be fairly important to clarify this.

Carsten Korth
David P., I think that the variety in DISC1-associated phenotypes relates to a very basic function of DISC1 upstream of more specific “phenotype-selector” traits that decide about a clinical disease phenotype. In that sense, DISC1 is a prime vulnerability factor for behavior rather than a strict one-disease associated gene/protein.

David Porteous
Carsten, agreed—so genotype/phenotype and structure/function become critical and exciting.

Peter Penzes
Has anybody charted the trajectory of phenotypes in any of the DISC1 mutant mice? is there a delayed onset of any of the disease-related phenotypes?

David St Clair
There is a delayed cognitive problem in the Aberdeen mice, but I have no details.

Akira Sawa
Peter, Minae Niwa presented data that phenotypes show up only after puberty by conducting behavioral assays both before and after puberty (as far as I am aware, presented at SfN 2009).

Peter Penzes
I wonder if the time course of any of the phenotypes emerges in “adolescence” to parallel the course of the human disease.

Akiko Hayashi
Peter, agreed. This is a very good criterion for a schizophrenia animal model.

Akira Sawa
David P. and David St Clair, would you please introduce, if available, an update of deep sequencing or efforts to find new rare variants on DISC1? Any updates?

Jon Wood
Following on from Misha's Pletnikov's initial comment, has anyone observed (or even looked for) glial abnormalities in mouse models This would help clarify which of the many changes seen in the animals are behaviorally relevant and ultimately guide further model development.

David Porteous
Peter/Akira/Akiko, the time course may differ from model to model—those that show more of a schizophrenia or bipolar/unipolar phenotype. What about the autism aspect?

David St Clair
My understanding from the last WCPG is that several groups have performed deep sequencing, and rare variants are overrepresented in cases. We have access to two cases with stop codons and at NIH will be looking at RNA transcripts. If anyone has additional samples, we can include them at the same time.

Akira Sawa
In autism, transient hypertrophy of the cortex (which eventually results in slightly smaller or normal size of brains) is important. Did somebody with DISC1 mice observe this phenotype? Just hypertrophy of cortex cannot be a model for autism.

Hakon Heimer
David St Clair and David P., do the people doing the cross-disorders analysis of the Psychiatric GWAS consortium indicate whether they see DISC1 signal in their early analyses?

David Porteous
Hakon, the big problem with the GWAS signal is that it only picks up common variants, and the SNPs we showed to be most relevant in European populations are poorly represented. Also, DISC1 signal will be distributed across many common and rare variants. David St Clair probably has the best insight on which studies are showing genetic signals.

David St Clair
Hakon, the GWAS have not picked up much in the way of common SNP signals from the DISC1 region, but as said, it is a big gene and many SNPs are missing.

Akira Sawa
David St Clair and David P., as well as everybody, how about epigenetic implication in DISC1 or DISC1 expression (for specific isoforms)?

David St Clair
Akira, I am not sure if anyone has looked, but reelin is in the pathway and it is, of course, epigenetically interesting.

Tatiana Lipina
We probed epigenetic drug on DISC1 mutants and did not find epigenetic-related changes on level of gene expression. Akira, does autism develop earlier than schizophrenia?

Akira Sawa
Tatiana, of course, autism is, clinically, in child psychiatry, whereas schizophrenia is an adult psychiatric disorder with neurodevelopmental influences in its etiology. (Recently, I’ve tried not to use the phrase “schizophrenia is a neurodevelopmental disorder” because people are now forgetting that this is an adult psychiatric condition.)

Tatiana Lipina
Thanks, Akira. It is interesting that many DISC1 animal models show impaired social behavior.

Nick Bradshaw
A couple of more general genetics questions: There have been several papers recently associating mutation in DISC1 interactors with psychiatric illness. 1) Do people believe that this is the next logical step if we are to uncover “druggable” DISC1 pathways; and 2) Do we think it will be possible to tie down specific interactors to specific DISC1-realted conditions and phenotypes (e.g., PDE4B was seen to be associated with schizophrenia but was negative for depression, while I seem to recall that pericentrin/kendrin is in a known bipolar linkage region).

David St Clair
Nick, the answer to your questions should be “yes” and “yes,” but it is a big undertaking from a genetics point of view since numbers of cases with mutations are small.

Amy Ramsey
David St Clair and Nick, I agree, but mouse genetics may be preferable to humans in this case.

David Porteous
Hakon/Akira, we had signalling down as a third topic. We have touched on it, but in the few minutes left, does anyone want to chip in on this topic?

Atsushi Kamiya
David, As to the signalosome, since there many DISC1-mediated signalings, RNAi technology may be useful. We can systematically use many RNAi which have different target sequences to dissect each signaling.

Hakon Heimer
All, we have reached the end of our official time, but time is different on the Internet (perhaps some of you are on laptops in the cafeteria!). At any rate, we can continue as long as we like, but those who must leave might like to make any closing statements.

David Porteous
Atsushi, I like your RNAi approach—faster and cheaper to test multiple hypotheses than making a new mouse model each time.

Akira Sawa
To address different signalosomes associated with DISC1, the key question is how DISC1 can switch from one signalosome to another. Although we did not touch so much on it, post-translational modification of DISC1 should be extremely important as a topic in the coming years.

Amy Ramsey
Akira, I agree with that last statement completely! Thank you for the helpful discussion.

David Porteous
Amy/Akira, I now think of the DISC1 complex as the pathway—space, time, and partner dependent.

Akira Sawa
I think we have only two or three minutes left. There should be a very important notice from David P. If you have a chance, David, please disclose this exciting notice soon.

David Porteous
Akira/everyone, thanks—yes, log onto www.disc2010.org and register/submit an abstract for the meeting in Edinburgh, 3-6 September 2010—be there!!

Hakon Heimer
David P. and David St Clair, we will all brush up on our imitation Scottish accents for the visit!

Andres Buonanno
Thank you, Akira and David—great chat.

David Porteous
Hakon, please post to SRF and all discussants! A wee dram of Scotch and some great science/discussion await all who come.

Patricio ODonnell
David and Akira, thanks for a stimulating discussion, as usual. I'm saving some space for some Haggis. :-)

Hakon Heimer
Thanks, David and Akira, again!

Tatiana Lipina
Thanks, Akira and David; it is very interesting to see updates on DISC1.

Amy Ramsey
Yes, absolutely. We will be working on that in the coming year.

Carsten Korth
Thanks, Akira, David P., and everybody!

David Porteous
All, thanks and goodbye.

Akira Sawa
Hakon and Nico, I wish to say thank you very much for your efforts in coordinating this roundtable session. With two major pioneers of this field (David), now it is very exciting. I will say goodbye and see you soon probably at DISC1-2010 Edinburgh!!

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