Schizophrenia-Related Neural and Behavioral Phenotypes in Transgenic Mice Expressing Truncated<i>Disc1</i>

Shen, Sanbing; Luo, Bing; Nakamoto, Chizu; Zhang, Feng; Pu, Jun; Kuan, Soh Leh; Chatzi, Christina; He, Suqin; Mackie, I C; Brandon, Nicholas J.; Marquis, Karen L.; Day, Mark L.; Hurko, Orest; McCaig, Colin; Riedel, Gernot; Clair, David St

doi:10.1523/jneurosci.3299-08.2008

Cited by 238 publications

(220 citation statements)

References 58 publications

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“…Loss of normal DISC1 function or expression of mutant DISC1 disrupts its interaction with NDEL1 and causes abnormal neurite outgrowth in PC12 cells (Ozeki et al, 2003;Kamiya et al, 2005). Consistent with this, transgenic mice expressing truncated Disc1 have an inhibition of neurite outgrowth and a reduction of apical dendritic length (Kvajo et al, 2008;Shen et al, 2008). We reported similar findings of significant reductions in dendritic length and surface area in our Disc1 mutants, further supporting the role of DISC1 in neurodevelopment.…”

Section: Discussionsupporting

confidence: 85%

Disc1Point Mutations in Mice Affect Development of the Cerebral Cortex

Lee¹,

Fadel²,

Preston-Maher³

et al. 2011

J. Neurosci.

116

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Disrupted-in-Schizophrenia 1 (DISC1) is a strong candidate gene for schizophrenia and other mental disorders. DISC1 regulates neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth, and neurotransmitter signaling. Abnormal neuronal morphology and cortical architecture are seen in human postmortem brain from patients with schizophrenia. However, the etiology and development of these histological abnormalities remain unclear. We analyzed the histology of two Disc1 mutant mice with point mutations (Q31L and L100P) and found a relative reduction in neuron number, decreased neurogenesis, and altered neuron distribution compared to wild-type littermates. Frontal cortical neurons have shorter dendrites and decreased surface area and spine density. Overall, the histology of Disc1 mutant mouse cortex is reminiscent of the findings in schizophrenia. These results provide further evidence that Disc1 participates in cortical development, including neurogenesis and neuron migration.

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Section: Discussionsupporting

confidence: 85%

Disc1Point Mutations in Mice Affect Development of the Cerebral Cortex

Lee¹,

Fadel²,

Preston-Maher³

et al. 2011

J. Neurosci.

116

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“…To our knowledge however, there is no data on anomalies of the GABAergic system along the longitudinal axis of patient's hippocampus. Decreased PV expression or abnormal maturation of FSI are observed in experimental animal models for schizophrenia (Penschuck et al, 2006;Behrens et al, 2007;Tseng et al, 2008;Lodge et al, 2009), and following environmental factors (Dell'Anna et al, 1996;Harte et al, 2007;Meyer et al, 2008) or manipulations of genes associated with schizophrenia (Hikida et al, 2007;Shen et al, 2008;Fisahn et al, 2009). However, the degree of PV impairment and the susceptible brain structures vary across models and depend on the time of manipulation.…”

Section: Discussionmentioning

confidence: 99%

Redox Dysregulation Affects the Ventral But Not Dorsal Hippocampus: Impairment of Parvalbumin Neurons, Gamma Oscillations, and Related Behaviors

Steullet¹,

Cabungcal²,

Kulak³

et al. 2010

J. Neurosci.

181

171

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Elevated oxidative stress and alteration in antioxidant systems, including glutathione (GSH) decrease, are observed in schizophrenia. Genetic and functional data indicate that impaired GSH synthesis represents a susceptibility factor for the disorder. Here, we show that a genetically compromised GSH synthesis affects the morphological and functional integrity of hippocampal parvalbumin-immunoreactive (PV-IR) interneurons, known to be affected in schizophrenia. A GSH deficit causes a selective decrease of PV-IR interneurons in CA3 and dendate gyrus (DG) of the ventral but not dorsal hippocampus and a concomitant reduction of ␤/␥ oscillations. Impairment of PV-IR interneurons emerges at the end of adolescence/early adulthood as oxidative stress increases or cumulates selectively in CA3 and DG of the ventral hippocampus. Such redox dysregulation alters stress and emotion-related behaviors but leaves spatial abilities intact, indicating functional disruption of the ventral but not dorsal hippocampus. Thus, a GSH deficit affects PV-IR interneuron's integrity and neuronal synchrony in a region-and time-specific manner, leading to behavioral phenotypes related to psychiatric disorders.

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“…Transfection of cells with truncated DISC1 isoforms results in aberrant intracellular localization of DISC1, disruption of interactions with other proteins, including NDEL1, LIS1, dynactin, dynein, and PDE4B, aberrant mitochondrial function, disrupted microtubular network, and inhibition of neurite outgrowth (26,53,55,57,59,60). Mice, in which C-terminally truncated forms of DISC1 were overexpressed on a background of endogenous mouse DISC1, show brain morphological changes, cytoarchitectural anomalies in the hippocampus and cortex, diminished neurite outgrowth, and various behavioral abnormalities reminiscent of aspects of human mental illness (61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms

Nakata

Lipska

Hyde

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

161

146

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Disrupted-In-Schizophrenia-1 (DISC1) is a promising susceptibility gene for major mental illness, but the mechanism of the clinical association is unknown. We searched for DISC1 transcripts in adult and fetal human brain and tested whether their expression is altered in patients with schizophrenia and is associated with genetic variation in DISC1. Many alternatively spliced transcripts were identified, including groups lacking exon 3 (⌬3), exons 7 and 8 (⌬7⌬8), an exon 3 insertion variant (extra short variant-1, Esv1), and intergenic splicing between TSNAX and DISC1. Isoforms ⌬7⌬8, Esv1, and ⌬3, which encode truncated DISC1 proteins, were expressed more abundantly during fetal development than during postnatal ages, and their expression was higher in the hippocampus of patients with schizophrenia. Schizophrenia risk-associated polymorphisms [non-synonymous SNPs rs821616 (Cys704Ser) and rs6675281 (Leu607Phe), and rs821597] were associated with the expression of ⌬3 and ⌬7⌬8. Moreover, the same allele at rs6675281, which predicted higher expression of these transcripts in the hippocampus, was associated with higher expression of DISC1⌬7⌬8 in lymphoblasts in an independent sample. Our results implicate a molecular mechanism of genetic risk associated with DISC1 involving specific alterations in gene processing.alternative splicing ͉ genetic ͉ hippocampus ͉ psychiatric illness S chizophrenia is a common mental disorder with a lifetime prevalence of Ϸ 1% (1). It has been assumed, on the basis of evidence from twin, family, and adoption studies, that genetic factors play a strong etiologic role in schizophrenia (2, 3). The genetic predisposition is likely to be determined by a complex network of interactions between genes and environmental risk factors (4).The Disrupted-In-Schizophrenia-1 (DISC1) gene was identified as a potential susceptibility gene for mental disorders based on studies of a chromosomal translocation found in a large Scottish family that had a high frequency of schizophrenia and other psychiatric disorders, including bipolar disorder and major depression (5-7). Although the translocation identified in the Scottish family has not been observed in any other families, independent support for involvement of DISC1 in the etiology of mental illness has come from a number of genetic linkage and association studies in diverse populations (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Although the specific SNPs, alleles, and haplotypes have varied across these studies, raising issues of allelic and populations heterogeneity, the overall evidence implicates DISC1 as a promising candidate susceptibility gene for schizophrenia. However, the mechanism by which DISC1 contributes to the pathophysiology of schizophrenia remains unknown. Although reduced expression of DISC1 mRNA was found in lymphoblastoid cell lines of family members with the translocation (26) and in bipolar disorder patients with a putative risk-associated haplotype (27), no changes were detected in the brain tissue of unre...

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Schizophrenia-Related Neural and Behavioral Phenotypes in Transgenic Mice Expressing TruncatedDisc1

Cited by 238 publications

References 58 publications

Disc1Point Mutations in Mice Affect Development of the Cerebral Cortex

Disc1Point Mutations in Mice Affect Development of the Cerebral Cortex

Redox Dysregulation Affects the Ventral But Not Dorsal Hippocampus: Impairment of Parvalbumin Neurons, Gamma Oscillations, and Related Behaviors

DISC1 splice variants are upregulated in schizophrenia and associated with risk polymorphisms

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