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

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

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