The gene encoding proline dehydrogenase modulates sensorimotor gating in mice

Abstract

Hemizygous cryptic deletions of the q11 band of human chromosome 22 have been associated with a number of psychiatric and behavioural phenotypes, including schizophrenia1,2,3. Here we report the isolation and characterization of PRODH, a human homologue of Drosophila melanogaster sluggish-A (slgA), which encodes proline dehydrogenase responsible for the behavioural phenotype of the slgA mutant4. PRODH is localized at chromosome 22q11 in a region deleted in some psychiatric patients. We also isolated the mouse homologue of slgA (Prodh), identified a mutation in this gene in the Pro/Re hyperprolinaemic mouse strain and found that these mice have a deficit in sensorimotor gating accompanied by regional neurochemical alterations in the brain. Sensorimotor gating is a neural filtering process that allows attention to be focused on a given stimulus, and is affected in patients with neuropsychiatric disorders5. Furthermore, several lines of evidence suggest that proline may serve as a modulator of synaptic transmission in the mammalian brain. Our observations, in conjunction with the chromosomal location of PRODH, suggest a potential involvement of this gene in the 22q11-associated psychiatric and behavioural phenotypes.

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Figure 1: Amino acid sequence, cross-specises comparison and mapping of PRODH .
Figure 2: Expression pattern of human PRODH, mouse and rat orthologues.
Figure 3: Effect of Prodh mutation on proline levels and exploratory behaviours.
Figure 4: Morphological and neurochemical analysis of Prodh–/– brains.
Figure 5: Sensorimotor gating in Prodh-/- mice.

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Acknowledgements

We thank B.L. Galke, Y. Jiao and L. Malinova for technical assistance; C. Baptista and A. Matilla for help in the initial phases of this work; M. Morgan and D. Pfaff for help with setting up the behavioural assays; M. McGee-Harper for help with the statistical analysis; and D. Pfaff for useful comments on the manuscript. Support for this work was provided by a grant from the Patterson Trust and the Irma T. Hirschl Foundation to M.K.

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Correspondence to Maria Karayiorgou.

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