The identification of rare mutations that result in predisposition to SCZ with relatively high penetrance has led to the development of mouse models of proven etiologic relevance. DISC1 is a susceptibility gene identified through a rare genetic lesion, a balanced chromosomal translocation segregating with SCZ and mood disorders in a large pedigree. We used a disease-focused knock-in approach to introduce a truncating lesion in the murine Disc1 orthologue designed to model the effects of this translocation. During the first round of this grant we showed that Disc1 mutant mice display specific and robust deficiencies in spatial working memory tests. We also uncovered widespread cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal pathfinding and are accompanied by changes in neural activity and short-term plasticity. We also showed that dysregulation of cAMP levels contributes to the structural connectivity deficits. Finally we provided evidence that mutant mice have altered functional connectivity of prefrontal areas with temporal lobe structures. Building on these findings, here we propose to complete our analysis on the effect of the Disc1 mutation on hippocampus, extend our structural and functional analysis to prefrontal cortex and finally analyze the effect of the modeled mutation on the communication between these two areas. In addition to our previous results from Disc1 mutant mice our proposed research is dictated by parallel analysis of other models of rare mutations, which affords the opportunity to compare results, identify key common pathways and enable development of a comprehensive and integrative model of schizophrenia pathogenesis and pathophysiology. This knowledge will facilitate discovery of novel treatments and biomarkers.

Public Health Relevance

Schizophrenia is a common and complex psychiatric disorder with a strong genetic component. This proposal is inherently translational in nature, aimed at identifying specific patterns of abnormal brain structure and function caused by schizophrenia predisposing genes. Identifying such patterns would facilitate novel approaches to therapies aimed at reversing the underlying pathophysiology and restoring normal function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH080234-06
Application #
8449589
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (98))
Program Officer
Panchision, David M
Project Start
2007-07-15
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$382,357
Indirect Cost
$142,357
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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
Arguello, P Alexander; Gogos, Joseph A (2012) Genetic and cognitive windows into circuit mechanisms of psychiatric disease. Trends Neurosci 35:3-13
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
Arguello, P Alexander; Gogos, Joseph A (2010) Cognition in mouse models of schizophrenia susceptibility genes. Schizophr Bull 36:289-300
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