Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice


Microdeletions of 22q11.2 represent one of the highest known genetic risk factors for schizophrenia. It is likely that more than one gene contributes to the marked risk associated with this locus. Two of the candidate risk genes encode the enzymes proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT), which modulate the levels of a putative neuromodulator (L-proline) and the neurotransmitter dopamine, respectively. Mice that model the state of PRODH deficiency observed in humans with schizophrenia show increased neurotransmitter release at glutamatergic synapses as well as deficits in associative learning and response to psychomimetic drugs. Transcriptional profiling and pharmacological manipulations identified a transcriptional and behavioral interaction between the Prodh and Comt genes that is likely to represent a homeostatic response to enhanced dopaminergic signaling in the frontal cortex. This interaction modulates a number of schizophrenia-related phenotypes, providing a framework for understanding the high disease risk associated with this locus, the expression of the phenotype, or both.

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Figure 1: Electrophysiological characterization of Prodh-deficient mice.
Figure 2: Behavioral characterization of Prodh-deficient mice.
Figure 3: RNA expression profiling in the frontal cortex of Prodh-deficient mice.
Figure 4: Validation of RNA expression profiling of Comt in Prodh-deficient mice.
Figure 5: Dopaminergic dysregulation in the frontal cortex of Prodh-deficient mice.
Figure 6: Dopamine-related signaling molecules in the frontal cortex of Prodh-deficient mice.
Figure 7: Epistatic interaction between Prodh and Comt at the behavioral level.


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The authors acknowledge C. Frazier and M. Sribour for technical support and assistance with the mouse colony, J. Chan for help with the behavioral analysis, M. Fazzini for help with the immunocytochemistry and the Sloan-Kettering Genomics Core Laboratory (A. Viale, Director) for help with expression profiling. This research was supported in part by the US National Institutes of Health (grant MH67068 to M.K. and J.A.G. and grant DA07418 to D.S.) and by the New York Academy of Sciences (J.A.G.). J.A.G. is also an EJLB Scholar, a Vicente Young Investigator of the National Alliance for Research on Schizophrenia and Depression (NARSAD) and the recipient of a McKnight Brain Disorders Award. S.S.Z. is a recipient of the NARSAD Young Investigator award and the Hereditary Disease Foundation postdoctoral fellowship. M.P. is supported in part by Telethon, Italy (fellowship no. GFP02011).

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Correspondence to Maria Karayiorgou or Joseph A Gogos.

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Paterlini, M., Zakharenko, S., Lai, W. et al. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat Neurosci 8, 1586–1594 (2005).

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