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DISC1 2010—Rodent Models Expand Knowledge of DISC1

As part of our ongoing coverage of DISC1 2010, held 3-6 September 2010, in Edinburgh, the United Kingdom, we bring you a meeting missive from Gareth Briggs, a graduate student at the University of Edinburgh.


21 September 2010. Plenary Session 4, chaired by Kirsty Millar, University of Edinburgh, was the first Neurodevelopment and Models Systems plenary session on Saturday afternoon. It focused on a broad array of DISC1 transgenic mouse models, with speakers discussing the further characterization of existing models (L100P,Q31L) and the use of established mouse models to study gene environment interactions.

The first talk, “Cognitive Deficits Caused by Disruption of DISC1 Specifically in Adult Neurons,” was given by Alcino Silva of the University of California, Los Angeles. Silva talked about two novel DISC1 mouse models, the first involving targeted shRNA DISC1 knockdown to neurons in the dentate gyrus of the hippocampus. Mice subjected to DISC1 shRNA show deficits in learning and memory, increased anxiety, and decreased social interaction. This knockdown of DISC1 can be partially rescued by treatment with rapamycin, an antagonist of the mTOR pathway. Rapamycin reverses alterations in learning, memory, and anxiety, but not in social interaction. The use of rapamycin in the shRNA DISC1 model demonstrates how defective DISC1 and associated phenotypes can be rectified by pharmaceuticals.

Silva’s’s second murine model expresses the N-terminal region of DISC1 selectively in the forebrain, in a similar paradigm to the C-terminal DISC1 model published by Weidong Li in his group (see SRF related news story). Adult induction N-terminal DISC1 results in increased activity in the open field test and depression-like behavior: reduced performance in the forced swim test and altered social behavior. The alterations in the behavior of both the shRNA and the N-terminal mice could be analogous to the abnormal range of cognition, mood, and behavior seen in patients with DISC1 disruption.

The University of Toronto’s Albert Wong presented on the altered neural morphology in the frontal cortex of the Q31L and L100P ENU point mutated DISC1 mutant mice in his talk, “Disc1 Point Mutations in Mice Alter Neuronal Distribution, Dendritic Morphology and Spine Density in the Frontal Cortex.” Q31L mice have a depression-like phenotype, whilst the L100P mice have a schizophrenia-like phenotype (see SRF related news story). Wong detects altered cortical neuron distribution along with shorter dendrites in the frontal cortex of both transgenic lines. BrdU staining for proliferation reveals reduced neurogenesis and mispositioning of neurons. The frontal cortex cellular phenotypes of the L100P and Q31L mice demonstrate how slight mutations in DISC1 can produce neurological abnormalities. Wong plans to investigate the upstream molecular mechanisms responsible for frontal cortex cellular phenotypes.

Some clues to the cellular neurogenic phenotypes of the L100P and Q31 mice may be found in a poster presented at the conference by Jayanth Chandran of University of Edinburgh. Chandran has studied neurospheres, structures formed from neural stem cells. Cortical neurons from newborn Q31L mice produce fewer neurospheres than do L100P mice, and neurospheres from newborn Q31L and L100P are smaller than wild-type. In adult Q31 and L100P mice, the number of neuroblasts in the subventricular zone is reduced, yet proliferation is normal. However, in the dentate gyrus of L100P mice, proliferation is reduced, while neuronal migration is accelerated. It appears that the L100P and Q31L mice have multiple defects in neurogenesis; the altered neurosphere size and number may reflect altered neuronal stem cell behavior.

Continuing the Saturday afternoon session, Sanbing Shen of Aberdeen University, U.K., gave a talk called, “Expression of Truncated DISC1 Associates with Schizophrenia‐Related Neural and Behavioral Phenotypes in Mice,” that covered the phenotype of his Disc1tr transgenic mice (see Shen et al., 2008). Shen has since moved on to a new project investigating a novel serine threonine kinase in collaboration with Douglas Blackwood of Edinburgh University. The novel kinase is expressed in brain regions neuropathologically relevant to schizophrenia, but it is not brain specific per se, and the kinase is also developmentally regulated. Interestingly, the middle and C-terminal regions of DISC1 co-immunoprecipitate with the novel kinase. Patients with schizophrenia have been identified that carry a deletion in the area encoding the second arm of the kinase.

The final speaker before the afternoon coffee break, Mikhail Pletnikov of Johns Hopkins University, Baltimore, Maryland, has created a richer model of mental illness combining genetic and environmental interactions. He has coupled an established mutant DISC1 transgenic model, which has inducible expression of mutant DISC1 (see SRF related news story), with a POLY I:C challenge. POLY I:C is a synthetic mRNA that mimics viral infection. In utero exposure to POLY I:C in conjunction with the mutant DISC1 transgene being expressed throughout development produces a diverse phenotype. An anxiety and depression-like is behavior is apparent. Anatomically, the spine density in the dentate gyrus of the hippocampus is reduced, as is the volume of the amygdala and peri-aquaductal gray. The enlargement of the lateral ventricles normally present in mutant DISC1 mice (Pletnikov et al. 2008) is attenuated following exposure to POLY I:C. Molecularly, endogenous GSK3β and cytokine levels are altered, the expression of mutant DISC1 is raised, while levels of endogenous DISC1 are reduced.

It appears that both prenatal and postnatal interactions are required for the creation of the mental illness-like phenotype in the POLY I:C mutant DISC1 model. When mutant DISC1 is expressed until the early postnatal period alongside Poly I:C, the behavioral phenotypes analogous to mental illness are absent. The behavioral phenotypes are also ameliorated if mutant DISC1 expression is activated from the post-weaning period onwards. In the future, Pletnikov aims to look at gene-environment interaction of drug abuse on the DISC1 pathway using methamphetamine, theorizing that the genetic factors predisposing individuals to schizophrenia overlap with those of addiction.

In the poster aisles
Two of the posters at the meeting described progress toward the eagerly awaited rat models of DISC1. Sigma Life Science’s SAGE Labs have used zinc finger nuclease fusion proteins to create rat transgenic DISC1 models. As reported in David Cleaver's poster, so far transgenics have been created that have either deletions in DISC1 exons 2 or 5, or the insertion of a premature stop codon in exon 5. Previously, transgenic rat models have been hard to produce, and the SAGE group is currently tackling problems with breeding.

Pekka Kallunki’s group at H. Lundbeck A/S, Denmark, aim to create a rat model of the t(1;11) translocation and also look at the function of DISC1 in the nervous system. To do this, they have identified the location of the rat DISC1 promoter and have used the promoter to express EGFP in the rat cortex. With the identification of the rat DISC1 promoter, lentiviral vectors encoding DISC1 amino acids 1-597 have then been created for use in vivo and in vitro.—Gareth Briggs.

 
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