Disturbances in neuronal circuit formation may underlie the pathology of schizophrenia. This notion is supported by the fact that many genetic risk factors for schizophrenia have roles in neurodevelopment. Some of them likely act in common molecular pathways, displaying synergistic effects on key phenotypes in neurodevelopment, such as dendritic development, in which abnormalities have been reported in schizophrenia. Furthermore, the interaction between genetic and environmental factors, such as viral infection, may play a role in the disease etiology. One example is the case of Disrupted-in-Schizophrenia-1 (DISC1), which plays a role in various cellular processes in the developing cerebral cortex by mediating interaction with other genetic risk factors, such as nuclear distribution element-like (NDEL1). To produce animal models in which the expression of multiple risk genes can be manipulated simultaneously, in utero gene transfer is a useful method. The feasibility of this technique for examining the effect of genetic insults on neuronal circuits and brain functions was confirmed by our preliminary data, which showed that knockdown of DISC1 in the developing prefrontal cortex (PFC) leads to the impairment of mesocortical dopaminergic maturation and cognition. Nonetheless, it is unclear which DISC1-mediated cell behaviors in the specific developmental period lead to these phenotypes. Thus, in this study, to examine the role of the DISC1 pathway in specific developmental periods, we will utilize in utero Cre/loxP-mediated inducible gene transfer system. We hypothesize that (1) inducible knockdown of DISC1 in post-migratory neurons (inducible DISC1 KD) in PFC may segregate a role for DISC1 in dendritogenesis, independent from the secondary effects of DISC1 in dendrites caused by disturbed cell proliferation and/or migration, which may be required for mesocortical dopamine maturation and proper cognitive functions, (2) DISC1-NDEL1 interaction may be necessary for dendritic development, as well as the establishment of dopamine circuit and cognition, and (3) virus infection in post-migratory stages may exacerbate the phenotypes displayed in inducible DISC1 KD mice. To address these hypotheses, first, we will examine the role of DISC1 on dendritic development, mesocortical dopamine maturation, and cognitive functions in mice in which DISC1 is selectively suppressed in post-migratory stages in PFC by in utero inducible RNAi transfer. Second, we will examine synergistic effects of DISC1 and NDEL1 on these phenotypes in which concomitant suppression of DISC1 and NDEL1 occurs in post-migratory stages. We will also examine DISC1-NDEL1 interaction by "rescue" experiments with overexpression of DISC1 lacking the NDEL1 binding domain. Finally, in order to test the combined effect of immune activation and inducible knockdown of DISC1, we will examine the effect of the injection of PolyI:C at post-migratory stages in inducible DISC1 KD mice. This study will be able to contribute to the identification of a genetic risk-mediated molecular pathway in the specific developmental periods which may lead to disease susceptibility.

Public Health Relevance

The interaction between genetic risks and environmental factors, such as viral infection, during brain development, may play a role in the etiology of schizophrenia. In this study, we will explore a role for DISC1, a major genetic risk factor for schizophrenia, in the specific cellular process in brain development, which may be crucial for the establishment of dopamine maturation and cognitive functions. We will also examine combined effects of genetic disturbance of DISC1 and immune activation. This study will be able to contribute to the identification of genetic risk-mediated molecular pathway in the specific developmental periods which leads to disease susceptibility.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH091230-03
Application #
8248277
Study Section
Special Emphasis Panel (ZMH1-ERB-L (02))
Program Officer
Panchision, David M
Project Start
2010-07-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
3
Fiscal Year
2012
Total Cost
$324,720
Indirect Cost
$126,720
Name
Johns Hopkins University
Department
None
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Saito, Atsushi; Ballinger, Michael D L; Pletnikov, Mikhail V et al. (2013) Endocannabinoid system: potential novel targets for treatment of schizophrenia. Neurobiol Dis 53:10-7
Taniguchi, Yu; Young-Pearse, Tracy; Sawa, Akira et al. (2012) In utero electroporation as a tool for genetic manipulation in vivo to study psychiatric disorders: from genes to circuits and behaviors. Neuroscientist 18:169-79
Ishizuka, Koko; Kamiya, Atsushi; Oh, Edwin C et al. (2011) DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature 473:92-6
Zoubovsky, Sandra P; Pogorelov, Vladimir M; Taniguchi, Yu et al. (2011) Working memory deficits in neuronal nitric oxide synthase knockout mice: potential impairments in prefrontal cortex mediated cognitive function. Biochem Biophys Res Commun 408:707-12
Kubo, Ken-Ichiro; Tomita, Kenji; Uto, Asuka et al. (2010) Migration defects by DISC1 knockdown in C57BL/6, 129X1/SvJ, and ICR strains via in utero gene transfer and virus-mediated RNAi. Biochem Biophys Res Commun 400:631-7