Functional Analysis of 22q11 Schiz. Susceptibility Genes

Columbia University Health Sciences, New York NY

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Abstract

DESCRIPTION (provided by applicant): 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.