Recent genetic studies provide strong support for the gene Disrupted-in-Schizophrenia-1 (DISC1) in mental illness. Additional data obtained primarily by in vitro studies suggested that DISC1 may play a key role in neurodevelopment and cell signaling by interacting with other proteins, including nuclear distribution E-like (NUDE-L) protein and phosphodiesterase 4B. Despite recent advances in the study of DISC1 function, several critical issues remain unanswered. We propose to utilize a unique and reliable mouse model that we have established in our laboratory, which closely mimics the translocation observed in an affected family while preserving endogenous proteins levels, in order to facilitate a better understanding of the physiological contribution of DISC1 in normal and abnormal brain development and function in the context of psychiatric disorders. Our main goals are to a) facilitate a better understanding of the contribution of DISC1 in neurodevelopment, as well as in synaptic transmission and plasticity and b) test whether existing in vitro results can be validated in vivo in the mouse model we have established. Our analysis promises to provide valuable insights into the ways DISC1 increases the risk of psychiatric disorders and at the same time provide a well-characterized animal model that can be used to test further hypotheses and facilitate future drug development efforts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH080234-04
Application #
7881628
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (90))
Program Officer
Panchision, David M
Project Start
2007-07-15
Project End
2012-03-31
Budget Start
2010-07-01
Budget End
2012-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$336,742
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Hartung, Henrike; Cichon, Nicole; De Feo, Vito et al. (2016) From Shortage to Surge: A Developmental Switch in Hippocampal-Prefrontal Coupling in a Gene-Environment Model of Neuropsychiatric Disorders. Cereb Cortex 26:4265-4281
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Lepagnol-Bestel, A M; Kvajo, M; Karayiorgou, M et al. (2013) A Disc1 mutation differentially affects neurites and spines in hippocampal and cortical neurons. Mol Cell Neurosci 54:84-92
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Kvajo, Mirna; McKellar, Heather; Drew, Liam J et al. (2011) Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice. Proc Natl Acad Sci U S A 108:E1349-58
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Kvajo, Mirna; McKellar, Heather; Arguello, P Alexander et al. (2008) A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. Proc Natl Acad Sci U S A 105:7076-81