Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans

Hikida, Takatoshi; Jaaro-Peled, Hanna; Seshadri, Saurav; Oishi, Keiji; Hookway, Caroline; Kong, Stephanie E.; Wu, Di; Xue, Rong; Andradé, Manuella; Tankou, Stephanie; Mori, Susumu; Gallagher, Michela; Ishizuka, Koko; Pletnikov, Mikhail V.; Kida, Satoshi; Sawa, Akira

doi:10.1073/pnas.0704774104

Cited by 397 publications

(378 citation statements)

References 44 publications

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“…It may be necessary to explore the utility of temporal or spatial genetic knockdowns to gain information about the importance of a number of genes in schizophrenia. Recent work with DISC1 confirms the value of this approach (Hikida et al, 2007;Pletnikov et al, 2007).…”

Section: Animal Preparations and Their Use In Schizophrenia Drug Discmentioning

confidence: 79%

“…This said, several of the models may prove useful for generating an increased understanding of the pathophysiology of schizophrenia. Arguably, the most informative genetic models appear to be the calcineurin conditional knockout mouse, the neuregulin hypomorphic mouse, and the recently described DISC1 mutant mouse (Stefansson et al, 2002;Miyakawa et al, 2003;Hikida et al, 2007). There are two drawbacks to the currently available genetic models that must be mentioned.…”

Section: Animal Preparations and Their Use In Schizophrenia Drug Discmentioning

confidence: 99%

See 1 more Smart Citation

The Evolution of Drug Development in Schizophrenia: Past Issues and Future Opportunities

Carpenter

Koenig

2007

Neuropsychopharmacol

186

128

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Section: Animal Preparations and Their Use In Schizophrenia Drug Discmentioning

confidence: 79%

Section: Animal Preparations and Their Use In Schizophrenia Drug Discmentioning

confidence: 99%

The Evolution of Drug Development in Schizophrenia: Past Issues and Future Opportunities

Carpenter

Koenig

2007

Neuropsychopharmacol

186

128

View full text Add to dashboard Cite

“…Although both groups identified increased lateral ventricle size in the absence of any change in total brain volume, Hikida et al 52 detected this abnormality only at 6 weeks of age and demonstrated, rather surprisingly, that by 3 months (when the transgene is no longer expressed) there is no detectable difference in lateral ventricle size between wildtype and transgenic animals. Pletnikov et al, 53 however, detected the increased lateral ventricle size in adult mice.…”

Section: The Phenotype Of Mouse Disc1 Variantsmentioning

confidence: 97%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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“…Studies in the maternal infection model, the DISC1 model, and prenatal exposure to methylazoxymethanol acetate (MAM), have shown that alterations of brain development during specific periods of pre or postnatal development produce discrete disruptions that lead to behavioral and neurochemical effects that include a decreased number of PVinterneurons (Hikida et al, 2007;Lodge and Grace, 2007;Meyer et al, 2007;Lodge et al, 2009). In the MAM model, where the mitotoxin is applied during interneuronal proliferation/migration stage, the number of PV-interneurons decreased in specific brain regions that correlated with alterations in oscillatory activity and decreased lateral inhibition in adulthood (Lodge et al, 2009).…”

Section: Neurodevelopmental Origins Of Schizophrenia: Activation Of Tmentioning

confidence: 99%

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

2009

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An imbalance in the redox-state of the brain may be part of the underlying pathophysiology in schizophrenia. Inflammatory mediators, such as IL-6, which can tip the redox balance into a prooxidant state, have been consistently found to be altered in schizophrenia patients. However, the relationship of altered redox-state to altered brain functions observed in the disease has been unclear. Recent data from a pharmacological model of schizophrenia suggest that redox and inflammatory imbalances may be directly linked to the pathophysiology of the disease by alterations in fast-spiking interneurons. Repetitive adult-exposure to the NMDA-R antagonist ketamine increases the levels of the proinflammatory cytokine interleukin-6 in brain which, through activation of the superoxide-producing enzyme NADPH-oxidase (Nox2), leads to the loss of the GABAergic phenotype of PV-interneurons and to decreased inhibitory activity in prefrontal cortex. This effect is not observed after a single exposure to ketamine, suggesting that the first exposure to the NMDA-R antagonist primes the brain such that deleterious effects on PVinterneurons appear upon repetitive exposures. The effects of activation of the IL-6/Nox2 pathway on the PV-interneuronal system are reversible in the adult brain, but permanent in the developing cortex. The slow development of PV-interneurons, while essential for shaping of neuronal circuits during postnatal brain development, increases their vulnerability to deleterious insults that can permanently affect their maturational process. Thus, in individuals with genetic predisposition, the persistent activation of the IL-6/Nox2 pathway may be an environmental factor that tips the redoxbalance leading to schizophrenia symptoms in late adolescence and early adulthood.

show abstract

Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans

Cited by 397 publications

References 44 publications

The Evolution of Drug Development in Schizophrenia: Past Issues and Future Opportunities

The Evolution of Drug Development in Schizophrenia: Past Issues and Future Opportunities

The DISC locus in psychiatric illness

Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex?

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