Hemizygous microdeletions of the 22q11.2 locus are among the most common chromosomal abnormalities. Individuals with the 22q11.2 microdeletion exhibit a spectrum of cognitive deficits. Notably, ~30% of children with the 22q11.2 microdeletion will develop schizophrenia or schizoaffective disorder in adolescence or early adulthood. The genetic basis of the cognitive deficits and psychiatric symptoms is under intense scrutiny. Our own efforts to identify schizophrenia-susceptibility genes from this locus were based on the assumption that variants in 22q11 genes may modulate disease risk in the general (karyotypically normal) population and used large family samples followed up by studies in appropriately designed mouse models. Our studies on the PRODH gene, in particular, along with independent confirmatory work by other labs have provided compelling evidence that deficiency in the levels of PRODH (and the ensuing increase in L-proline levels) is an important contributor to the psychotic and possibly cognitive symptoms associated with the 22q11 microdeletions. Here, we propose to analyze in depth the effects of two additional biological processes that we discovered to be affected as a result of the 22q11 microdeletions, which are likely to affect neuronal development, synaptic plasticity and protein abundance of several brain expressed genes. Specifically, we propose to utilize three reliable mouse models recently generated in our labs and a series of sophisticated morphological, electrophysiological and behavioral approaches to facilitate a better understanding in vivo of how these two important physiological processes impaired by the 22q11 microdeletions, affect the function of hippocampus and prefrontal cortex, two brain regions implicated in the pathogenesis of schizophrenia and especially the cognitive endophenotypes associated with this disorder. Our proposed analysis promises to provide valuable insights on the ways the 22q11 locus increases the risk of schizophrenia and related impaired cognitive endophenotypes. Our proposed research will also provide well-characterized animal models that can be used to test further hypotheses and facilitate future drug development efforts. Indeed, a major motivation for this proposal is to exploit existing genetic knowledge to identify new drug targets that will improve currently available treatments.

Public Health Relevance

Microdeletions of the 22q11.2 locus are the highest known genetic risk factor for development of schizophrenia and related cognitive impairments. Our genetic studies thus far have allowed us to uncover a handful of genes that are likely to account for the observed increased risk. Since schizophrenia and related cognitive disorders affect a substantial proportion of the population and cause severe, long-term disability, it is imperative to pursue genetic research that will shed light on the causes and will allow meaningful intervention and development of successful treatments. The funding requested here will allow us to study in detail, in vivo in a real organism, the 2 novel pathophysiological mechanisms that we have uncovered thus far and generate pre-clinical mouse models that can be used for appropriately targeted drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH067068-10
Application #
8196900
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (90))
Program Officer
Meinecke, Douglas L
Project Start
2002-12-01
Project End
2013-08-07
Budget Start
2011-12-01
Budget End
2013-08-07
Support Year
10
Fiscal Year
2012
Total Cost
$565,105
Indirect Cost
$214,108
Name
Columbia University (N.Y.)
Department
Psychiatry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Xu, Bin; Hsu, Pei-Ken; Stark, Kimberly L et al. (2013) Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion. Cell 152:262-75
Fenelon, Karine; Xu, Bin; Lai, Cora S et al. (2013) The pattern of cortical dysfunction in a mouse model of a schizophrenia-related microdeletion. J Neurosci 33:14825-39
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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
Drew, Liam J; Crabtree, Gregg W; Markx, Sander et al. (2011) The 22q11.2 microdeletion: fifteen years of insights into the genetic and neural complexity of psychiatric disorders. Int J Dev Neurosci 29:259-81
Fenelon, Karine; Mukai, Jun; Xu, Bin et al. (2011) Deficiency of Dgcr8, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex. Proc Natl Acad Sci U S A 108:4447-52
Sigurdsson, Torfi; Stark, Kimberly L; Karayiorgou, Maria et al. (2010) Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia. Nature 464:763-7

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