This paper is an update on the original report from the Gogos group (Koike et al., 2006) on the phenotype of mice carrying a genetically modified version of the 129 strain derived Disc1 gene and joins an already impressive list of Disc1 mouse models with associated SZ related phenotypes. Koike et al. (2006) attempted to knock out the Disc1 locus by homologous recombination in 129 derived mouse embryonal stem cells. The objective was to mimic as best as possible the effect of the t(1;11) balanced translocation that segregated with SZ and related major mental illness in a large Scottish family (Blackwood et al., 2001) and which led to the identification at the breakpoint of the DISC1 gene (Millar et al., 2000). In the event, this didn’t quite happen as planned, but a fortuitous and positive outcome was the generation of a transgene insertion which introduced two termination codons in exons 7 and 8. Simultaneously, it was recognized that the Disc1 locus in the 129 strain actually already carries a 25 bp deletion, so is naturally a “knockout” of sorts.

The 129 mouse strain is well known to have a number of behavioral differences relative to the C57Bl6 strain. Backcrossing the transgene modified 129 Disc1 allele onto a C57Bl6 background allowed the Gogos group to isolate the Disc1 locus effect from the overall 129 strain effects. They reported that mice either heterozygous or homozygous for the transgene modified 129 Disc1 allele showed a deficit in a choice delay measure of working memory compared to C57Bl6 mice. A flurry of further Disc1 mouse models followed, with a ubiquitous and a conditional transgene model overexpressing a 5’ truncate DISC1 transgene from the Sawa and Ross groups at Johns Hopkins (Hikida et al., 2007; Pletnikov et al., 2008), an inducible C-terminal truncate DISC1 transgenic overexpression model from the Cannon group (Li et al., 2007), and two different ENU-induced Disc1 missense mutants from the Roder group (Clapcote et al., 2007). A rather consistent picture emerges from these studies of brain morphological and working memory deficits consistent with the neurodevelopmental hypothesis in SZ. Uniquely to date, the ENU missense mutation study of Clapcote et al. (2007) demonstrated behavioral effects that could be partially or wholly rescued by antipsychotic or antidepressant treatment. Furthermore, the missense mutations affected binding sites for the DISC1 interactor PDE4B, offering a molecular mechanism to explain the behavioral and drug effects.

So what does the latest study from Kvajo et al. (2008) add to the existing picture? Before examining this, it is appropriate to make one or two qualifying comments about this specific model. The reported effects apply only to the transgenically modified 129 Disc1 allele. It remains unclear what are the molecular, developmental, and behavioral consequences of the native 129 deletion allele of Disc1. Also, it remains uncertain to what extent this model and other transgenic overexpression models (Hikida et al., 2007; Pletnikov et al., 2008) “mimic” or “model” the molecular nature and phenotypic consequences of the SZ-associated human t(1;11) translocation. The original report suggested no brain morphological differences from wild-type, but more careful and detailed examination now reveals localized abnormalities, notably in the organization of newly born and mature neurons in the dentate gyrus. These results both resonate with and somewhat contradict earlier reports (Kamiya et al., 2005; Duan et al., 2007) that RNAi-mediated downregulation of Disc1 leads to abnormal neuronal migration and integration. Most likely, these differences reflect experimental differences (lifetime vs. transient downregulation of Disc1; cell autonomous vs. field effects). These issues will only be resolved by further study for which the availability of inducible transgenic models (Pletnikov et al., 2008; Li et al., 2007) will prove valuable.

The subtle neurodevelopmental abnormalities reported by Kvajo et al. (2008) were accompanied by abnormal short-term (but not long-term) potentiation in CA3CA1 synapses. Behavioral tests confirmed the previous report of a selective impairment of working memory. To conclude, this latest report adds to the rich evidence base that in the mouse Disc1 plays a crucial, if subtle neurodevelopmental role, which impacts on working memory. Taken alongside the other mouse models now available and others waiting in the wings, the field of SZ research can but benefit from their availability and the capacity they bring to construct and test hypotheses not possible in cell-based systems or ethically acceptable in human subjects. It is now timely and possible to explore and integrate in fine detail the neurodevelopmental, behavioral, neurophysiological, and pharmacological aspects of these models for what that may tell us about SZ. Importantly, with these various models to hand, it is also possible to examine fetal programming, epigenetic and environmental hypotheses predicted to exacerbate (or protect against) the neurodevelopmental and cognitive antecedents of SZ and their correlates in the mouse.

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

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, Wilson-Annan JC, Anderson S, Christie S, Taylor MS, Semple CA, Devon RS, Clair DM, Muir WJ, Blackwood DH, Porteous DJ. Disruption of two novel genes by a translocation co-segregating with schizophrenia. Hum Mol Genet. 2000 May 22;9(9):1415-23. 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. 2008 Feb 1;13(2):173-86, 115. 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

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

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 David J. Porteous

A leading group studying DISC1, led by Drs. Gogos and Karayiogou, has recently published an intriguing paper on further characterization of mice with genetic mutation/modulation in the Disc1 gene (first described in Koike et al., 2006). I would like to applaud their outstanding and detailed analyses in the manuscript, which obviously provides great benefits to the field. The methodologies that this group employed in this paper would be useful for future studies in modeling mice for psychiatric disorders. However, there are a couple of points in the descriptions in the Discussion section which I would like to comment on for a general audience.

First, isoform disposition of DISC1 is very complex. As Dr. Barbara Lipska has presented in academic conferences from her studies, there seem to be many more DISC1 isoforms than we predicted. Thus, unless one makes knockout mice in which the deleted region of the genome is clearly demonstrated by experimental data, we cannot draw any conclusion on whether or not the mice have no major allele(s) of Disc1. In this sense, although it is obvious that the mice presented in this manuscript are useful and beneficial for the basic understanding of DISC1, it is totally unclear whether or not major Disc1 isoforms are depleted in the mice reported in this manuscript. There is, in contrast, a published paper in which many laboratories tested their own “self-made” antibodies, the specificity of which was very carefully controlled in 129 and B6 mice (Ishizuka et al., 2007). More extensive comparison of Disc1-related reagents and mice among researchers will facilitate the progress of this field.

Second, the authors cited the paper by Kamiya et al. (Kamiya et al., 2005) incorrectly. The collaborative team among Pletnikov's, Song's, and our labs proposes that knockdown expression of Disc1 in the developing cortex leads to delayed migration, compared with accelerated migration in adult dentate gyrus (Duan et al., 2007). As Kamiya’s study utilized shRNA against exons 6 and 10, whereas Song/Duan’s study used shRNA against exon 2, we cannot fully exclude the possibility that the differences are coming from isoform-specific effects. This collaborative team at Johns Hopkins is currently addressing roles for DISC1 in several contexts of neurodevelopment in a systematic manner, including trials of shRNA targeting different portions of Disc1 (probably targeting different isoforms of Disc1) to various neurodevelopmental contexts, such as developing cerebral cortex and adult dentate gyrus. Because the mice presented in this paper depleted some, but not all, major isoforms, the phenotypic differences should be discussed in regional/context/isoform-specific manners. Nonetheless, the overall contribution of this paper is a great one for the field.

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

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 Akira Sawa